Pyranoindole derivatives, compositions and method of use

ABSTRACT

Pyranolindole and thiopyranoindole derivatives characterized by having an amino(lower)alkyl radical attached to either or both the 1 and 9 position of a pyrano[3,4-b]indole or thiopyrano[3,4-b]indole nucleus or having said radical attached to the 1 position of pyrano[4,3-b]indole or thiopyrano[4,3-b]indole nucleus are disclosed. The amino portion of the amino(lower)alkyl radical may be further substituted with one or two lower alkyl groups or incorporated into a heterocyclic amine radical. The derivatives having the amino(lower)alkyl radical only at position 1 are further substituted at position 1 and may be optionally substituted at positions 3,4,5,6,7,8, and 9. The pyrano[3,4-b]indole or thiopyrano[3,4-b]indole derivatives having the amino(lower)alkyl radical only at position 9 possess two substituents at position 1 and may be optionally substituted at position 3,4,5,6,7, and 8; the derivatives having an amino-(lower)alkyl radical at both positions 1 and 9 are further substituted at position 1 and may be optionally substituted at positions 3,4,5,6,7 and 8. The pyrano- and thiopyranindole derivatives of this invention are useful antidepressant and antiulcer agents. Methods for the preparation and use of these derivatives are also disclosed.

This is a division, of application Ser. No. 555,906, filed Mar. 5, 1975now U.S. Pat. No. 4,003,913 issued Jan. 18, 1977 which is acontinuation-in-part of each of our earlier filed applications, patentapplication Ser. No. 377,837, filed July 9, 1973 now U.S. Pat. No.3,880,853, issued Apr. 29, 1975 and patent application Ser. No. 217,627,filed Jan. 13, 1972 (now U.S. Pat. No. 3,852,285, issued Dec. 3, 1974).

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to novel pyranoindole and thiopyranoindolederivatives, to processes for their preparation and to intermediatesused in these processes.

More specifically, the present invention relates to novel pyranoindoleand thiopyranoindole derivatives possessing valuable pharmacologicproperties. For example, these derivatives exhibit useful antidepressantproperties at dosages which do not elicit undesirable side effects.Furthermore the present derivatives exhibit properties useful for thetreatment and prevention of ulcers. The combination of thesepharmacologic properties together with a low order of toxicity renderthe pyranoindoles and thiopyranoindoles of the invention therapeuticallyuseful.

2. Description of the Prior Art

Only a rather limited number of reports dealing with pyranoindolederivatives are available. In the few that do exist, pyranoindoles aretreated more in the manner of chemical curiosities. For the most partthese reports discuss the preparation of pyranoindoles in which thepyran portion thereof exists as a lactone. For example, see H.Plieninger, Chem. Ber., 83, 271 (1950), S. Sakurai and T. Ito, NipponKagaku Zasshi, 78, 1665 (1957); [Chem Abstr., 54, 1488f (1960)], and J.Szmuszkovicz, J. Org. Chem., 27, 511 (1962).

The thiopyranoindoles of the prior art, for example,5-(3-aminopropyl)-1,3,4,5-tetrahydrothiopyrano[4,3-b]indole, M.E. Freed,et al., J. Med. Chem., 7, 628 (1964) are distinguished from the presentcompounds of this invention by lacking substituents on the thiopyranring.

SUMMARY OF THE INVENTION

The pyranoindole and thiopyranoindole derivatives of this invention arecharacterized by having an amino(lower)alkyl radical attached to apyranoindole or thiopyranoindole nucleus. The preferred derivatives ofthis invention are represented by formula I and Ia ##STR1## in which R¹is lower alkyl or lower cycloalkyl; R², R³, R⁴ and R⁵ are the same ordifferent selected from the group consisting of hydrogen and loweralkyl; R⁶ is hydrogen, lower alkyl hydroxy, lower alkoxy, loweralkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl, lower alkenyl,propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula--Alk--NR⁸ R⁹ wherein Alk is an alkylene selected form the groupconsisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ andR¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are either the same ordifferent selected from the group consisting of hydrogen and loweralkyl, or R⁸ is lower alkyl and R⁹ is p-chlorophenacyl or R⁸ and R.sup.9 together with the nitrogen atom to which they are joined form aheterocyclic amine radical selected from the group consisting of1-pyrrolidinyl, piperidino, morpholino, piperazino,4-(lower-alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl;X is oxy or thio; and Y is lower alkyl, phenyl(lower)alkyl or anamino(lower)alkyl radical of formula --Alk--NR⁸ R⁹ wherein Alk is analkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹²R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or loweralkyl and R⁸ and R⁹ are as defined herein; with the provisos that atleast one of R⁷ and Y is --Alk--NR⁸ R⁹ and that in the compounds offormula Ia, Y must be --Alk--NR⁸ R⁹ as defined herein.

In the above definitions it is understood that Alk, R⁸ and R⁹ in eachcase are entitled to the full range of their definitions as listedabove, so that Alk, R⁸ and R⁹ of Alk--NR⁸ R⁹ linked to position 9 offormula I need not necessarily be the same as Alk, R⁸ and R⁹ of Alk--NR⁸R⁹ linked to position 1.

Various processes for the preparation of the compounds of formula I aredisclosed.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates both straight andbranched chain alkyl radicals containing from one to six carbon atomsand includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,2-methylpentyl and the like.

The term "lower alkyl" as used herein contemplates both straight andbranched chain alkenyl radicals containing from two to six carbon atomsand includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-2-butenyl andfrom one to six carbon atoms and includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, 2-methylpentyl and the like.

The term "lower alkenyl" as used herein contemplates both straight andbranched chain alkenyl radicals containing from two to six carbon atomsand includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-3-butenyl andthe like.

The term "phenyl(lower)alkyl" as used herein contemplates a phenylalkylradical in which the alkyl portion thereof contains from one to fourcarbon atoms and includes benzyl, phenethyl, α-methylphenethyl and thelike.

The term "lower cycloalkyl" as used herein contemplates saturated cyclichydrocarbon radicals containing from three to six carbon atoms andincludes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term "lower alkoxy" as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy, ethoxy, isopropoxy and the like.

The term "lower alkanoyloxy" as used herein contemplates both straightand branched chain alkanoyloxy radicals containing from two to sixcarbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and thelike.

The term "halo" as used herein contemplates halogens and includesfluorine, chlorine, bromine and iodine.

The compounds of this invention are capable of forming acid additionsalts with pharmaceutically acceptable acids. Such acid addition saltsare included within the scope of this invention.

The acid addition salts are prepared by reacting the base form of theappropriate compound of formula I or Ia with either one to fourequivalents, depending on the number of basic nitrogens in the compound,or preferably with an excess of the appropriate acid in an organicsolvent, for example, ether or an ethanol-ether mixture. These salts,when administered to mammals, possess the same pharmacologic activitiesas the corresponding bases. For many purposes it is preferable toadminister the salts rather than the base compounds. Among the acidaddition salts suitable for this purpose are salts such as the sulfate,phosphate, lactate, tartrate, maleate, citrate, hydrobromide andhydrochloride. Both the base compounds and the salts have the distinctadvantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of thecompounds of formulae I and Ia which result from asymmetric centers,contained therein. These isomeric forms are prepared by differentmethods and are purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractionalcrystallization of the diastereoisomeric salts formed thereof, forinstance, with d- or l- tartaric acid or D-(+)-α-bromocamphor sulfonicacid, are also included.

ANTIDEPRESSANT ACTIVITY

The useful antidepressant activity of the compounds of formulae I and Iaand their acid addition salts with pharmaceutically acceptable acids aredemonstrated in standard pharmacologic tests, such as, for example, thetests described by F. Hafliger and V. Burckhart in"Psychopharmacological Agents", M. Gordon, Ed., Academic Press, New Yorkand London, 1964, pp. 75- 83.

More specifically, as noted in the latter reference the antidepressantproperties of a compound may be demonstrated by its capacity toantagonize the depressant effects of reserpine. Furthermore, it is welldocumented that reserpine in animals produces a model depression whichcan be used for detecting antidepressant properties. Accordingly, thecompounds of the present invention antagonize reserpine effects in miceat doses ranging from about 1 to 100 mg/kg. Several of the preferredcompounds, for instance,

1-[(2-dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indoleoxalate (Example 309),

1-methyl-[3-(methylamino)propyl]-1,3,4,9-tetrahydropyrano-[3,4-b]indoleoxalate (Example 310),

1-[3-(dimethylamino)propyl]-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indoleoxalate (Example 312),

1-[2-(dimethylamino)ethyl]-1-propyl-1,3,4,9-tetrahydropyrano-[3,4-b]indolemaleate (Example 330),

1-[2-(dimethylaminoethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydropyrano-[3,4-b]indolemaleate (Example 683), and

1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indolehydrochloride (Example 911), antagonize the effects of reserpine in miceat dose ranges from about 1 to 15 mg/kg.

When the compounds of this invention are used as antidepressants inwarm-blooded mammals, e.g. rats and mice, they may be used alone or incombination with pharmacologically acceptable carriers, the proportionof which is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard biologicalpractice. For example, they may be administered orally in solid formcontaining such excipients as starch, milk sugar, certain types of clayand so forth. They may also be administered orally in the form ofsolutions or they may be injected parenterally. For parenteraladministration they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. In general,the compounds of this invention are given at a concentration level thatwill afford an effective dose without causing any harmful or deleteriousside effects and preferably at a level that is in a range of from about0.1 mg to about 50 mg per kilo per day, although as aforementionedvariations will occur. However, a dosage level that is in the range offrom about 0.5 mg to about 25 mg per kilo per day is most desirablyemployed in order to achieve effective results.

ANTIULCER ACTIVITY

The compounds of this invention possess another useful pharmacologicproperty; that is, they are useful antiulcer agents. More particularly,the said compounds of this invention exhibit antiulcer activity instandard pharmacologic tests, for example, the test described by D. A.Brodie and L. S. Valitski, Proc. Soc. Exptl. Biol. Med., 113, 998(1963), based on the prevention of stress-induced ulcers.

When these compounds are employed as antiulcer agents, they areformulated and administered in the same manner as described above fortheir use as antidepressant agents.

PROCESSES

For the preparation of the pyranoindole and thiopyranoindole derivativesof formula I we prefer to use as starting materials the compounds ofgeneral formula II, ##STR2## in which R², R³, R⁴, R⁵, R⁶ and R⁷ are asdefined in the first instance and X¹ is hydroxy, mercapto, --S--SO₃ --Naor --S--SO₃ K.

The starting materials of formula II in which X¹ is hydroxy are eitherknown, for example, tryptophol, described by H. R. Snyder and F. J.Pilgrim, J. Am. Chem. Soc. 70, 3770 (1948), or they are obtained by thefollowing process: ##STR3##

With reference to this process phenylhydrazines of formula III and thehydroxyaldehyde of formula IV are reacted together according to theconditions of the "Fischer Indole Synthesis", for example, see P. L.Julian, E. N. Myer and H. C. Printy, "Heterocyclic Compounds", R. C.Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp.8- 11, to form the desired starting material (II, X¹ = OH).

The phenylhydrazines of formula III are either known or are preparedaccording to known methods. A convenient method involves thediazotization of the appropriately substituted aniline to give thecorresponding diazo derivative. The latter compound is then reduced withstannous chloride or sodium sulfite to give the correspondingphenylhydrazine, see L. F. Fieser and M. Fieser, "Advanced OrganicChemistry", Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example,"Rodd's Chemistry of Carbon Compounds", S. Coffey, Ed., Vol I d, 2nded., Elsevier Publishing Co., Amsterdam, 1965, pp. 44- 49, or they areprepared according to known methods. A convenient method involvesreduction of an appropriate lactone of formula ##STR4## withbis-(3-methyl-2-butyl)borane, H. G. Brown and D. B. Bigley, J. Am. Chem.Soc., 83, 486 (1961), diisobutyl aluminum hydride, L. I. Zakharkkin andI. M. Khorlina, Tetrahedron Letters, 619 (1962) or sodium aluminumhydride, L. I. Zakharkin et al., Tetrahedron Letters, 2087 (1963). Theappropriate lactones utilized in this condensation are eithercommercially available, for example, δ-valerolactone,α-methyl-butyrolactone, or they are described with a variety of methodsfor their preparation in organic chemistry textbooks; such as thetextbooks, "Methoden der Organischen Chemie", Houben-Weyl, E. Muller,Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561- 852 or L.F. Fieser and M. Fieser, "Advanced Organic Chemistry", cited above.

Alternatively, the starting materials of formula II in which R², R³, R⁴and R⁷ are hydrogen and X¹ is hydroxy are prepared by lithium aluminumhydride reduction (N. G. Gaylord, "Reduction with Complex MetalHydrides", Interscience Publishers, Inc., New York, 1956, pp. 322- 370)of compounds of formula V described by T. Y. Shen, U.S. Pat. No.3,161,654, Dec. 15, 1964: ##STR5## wherein R¹⁸ is lower alkyl and R⁵ andR⁶ are as defined in the first instance.

In addition, convenient processes are available for the specificsynthesis of certain starting materials of formula II. For example,starting materials of formula II in which R², R³, R⁴, R⁵ and R⁷ arehydrogen and X¹ is hydroxy are obtained by reduction of the appropriateethyl 3-indoleglyoxylate with lithium aluminum hydride, British Patent778,823 and T. Nogrady and T. W. Doyle, Can. J. Chem., 42, 485 (1964).Starting materials of formula II in which R² and R⁴ are hydrogen, R³, R⁵and R⁷ are hydrogen or lower alkyl and X¹ is hydroxy are obtained byreacting indole or an appropriately substituted indole with ethyleneoxide or lower alkyl substituted ethylene oxide according to the processof M. Julia et al., Bull. Soc. Chim. Fr., 2291 (1966).

The starting materials of formula II in which X¹ is mercapto, --S--SO₃Na or --S--SO₃ K, and R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in thefirst instance are obtained by the following process: The appropriatecompound of formula 11 (X¹ =OH) described above, is treated withphosphorus tribromide in an inert solvent, for example, ether ormethylene chloride to afford the corresponding 3-(2-bromoethyl)-indolederivative. The latter compound is then converted to the desiredstarting material of formula II (X¹ = SH) by a procedure similar to thatdescribed by N. N. Suvorov and V. N. Buyanov, Khim.-Farm. Zh., 1,(1967), [Chem. Abstr. 67, 73474a (1967)], for converting3-(2-bromoethyl)-indole to indole-3-ethanethiol (II; R², R³,R⁴, R⁵ andR⁶ = H and X¹ = SH). Accordingly, the appropriate3-(2-bromoethyl)-indole derivative is treated with sodium or potassiumthiosulfate to afford the corresponding sodium or potassiumβ-(3-indoly)ethyl thiosulfate derivative, respectively; namely thedesired starting materials of formula II (X=--S--SO₃ Na or --S--SO₃ K).Treatment of the latter product with strong alkali, for example, sodiumor potassium hydroxide, yields the correspondingbis[ω-(3-indolyl)ethyl]-disulfide derivative. Reduction of the lattercompound with lithium aluminum hydride gives the desired compounds offormula II (X¹ = SH).

Alternatively, the preceding thiosulfate derivative is treated withacid, for example, dilute aqueous solutions of hydrochloric acid,sulfuric acid or phosphoric acid, to give directly the latter compoundof formula II.

It should be noted that the preceding processes may not be entirelypractical for the preparation of the compounds of formula II in which X¹is mercapto, --S--SO₃ Na or --S--SO₃ K, and R⁶ is hydroxy or loweralkanoyloxy. For this reason, the preferred starting materials offormula II for the ultimate preparation of the compounds of formula I inwhich R⁶ is hydroxy or lower alkanoyloxy and X is thio are thecorresponding compounds of formula II in which R⁶ is benzyloxy, i.e., ahydroxyl with a protecting benzyl group or other suitable protectinggroup, see J. F. McOmie, "Advances in Organic Chemistry", Vol. 3, R. A.Raphael, et al, Ed., Interscience Publishers, New York, 1963, pp. 191-294. When the latter compounds are used as starting materials in thismanner, they are first subjected to the process (II + VI→VII), describedbelow. Subsequently, the benzyloxy group is removed by hydrogenation, inthe presence of a catalyst, for example, 10% palladium on carbon, justprior to affording the desired corresponding compound of formula I inwhich R⁶ is hydroxy. The latter are converted, if desired, to thecorresponding compound of formula I in which R⁶ is lower alkanoyloxy byconventional means, for example, by treatment with the appropriate loweralkanoic anhydride preferably in the presence of pyridine. Likewise, itshould be noted that similar use of the starting materials of formula IIin which X¹ is hydroxy and R⁶ is benzyloxy to obtain the correspondingcompound of formula I in which R⁶ is hydroxy or lower alkanoyloxy isalso preferred.

The above described starting materials of formula II in which R², R³,R⁴, R⁵, , R⁷ and X¹ are as defined in the first instance are nowsubjected to a key reaction comprising the treatment of said startingmaterials with a compound of formula ##STR6## in which R¹ is as definedin the first instance and Z is selected from the group consisting of:

a. COOR¹⁹ and Alk¹ -- COOR¹⁹ in which R¹⁹ is hydrogen or lower alkyl andAlk¹ is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰R¹¹ CR¹² R¹³ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ wherein R¹⁰, R¹¹, R¹², R¹³,R¹⁴ and R¹⁵ are hydrogen or lower alkyl,

b. CONR⁸ R⁹ and Alk¹ --CONR⁸ R⁹ in which Alk¹, R⁸ and R⁹ are as definedabove,

c. CH₂ OCOR²⁰ and Alk¹ --CH₂ OCOR²⁰ in which R²⁰ is hydrogen or loweralkyl and Alk¹ is as defined above,

d. Alk² --L in which Alk² is an alkylene selected from the groupconsisting of CR¹⁰ R¹¹ CHR¹², CR¹⁰ R¹¹ CR¹² R¹³ CHR¹⁴ and CR¹⁰ R¹¹ CR¹²R¹³ CR¹⁴ R¹⁵ CHR¹⁶ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are asdefined above and L is halo,

e. Alk NR⁸ COR²¹ in which Alk and R⁸ are as defined in the firstinstance and R²¹ is hydrogen or lower alkyl containing from one to fivecarbon atoms,

f. Alk-- NO₂ in which Alk is as defined in the first instance,

g. Lower alkyl and phenyl(lower)alkyl, and

h. Alk-- NR⁸ R⁹ in which Alk, R⁸ and R⁹ are as defined in the firstinstance, in the presence of an acid catalyst to yield the compounds offormula VII in which R¹, R², R³, R⁴, R⁵ R⁶, R⁷, X and Z are as definedabove. ##STR7##

Thereafter the appropriate compound of formula VII is converted to thedesired pyranoindole of formula I according to the processes describedhereinafter or is actually the desired compound of formula I in the casewhere Z is Alk--NR⁸ R⁹, as described above.

In practising the condensation (II + VI → VII) a solvent is usedgenerally as a reaction medium. Any solvent inert to the reactionconditions may be used. Suitable solvents include aromatic hydrocarbon,for example benzene, or toluene, ethers and cyclic ethers, for examplediethyl ether, dioxan, or tetrahydrofuran, halogenated hydrocarbons, forexample methylene dichloride, or carbon tetrachloride and the like.Benzene and tetrahydrofuran are especially convenient and practical forthis use. A variety of suitable acid catalysts may be used for thiscondensation, for example, the type of catalyst used in a Friedel-Craftsreaction, i.e. p-toluenesulfonic acid, aluminum chloride, phosphoruspentoxide, boron trifluoride, zinc chloride, hydrochloric acid,perchloric acid, trifluoroacetic acid, sulfuric acid and the like.p-Toluenesulfonic acid, aluminum chloride, boron trifluoride andphosphorus pentoxide are included among the preferred acid catalysts.The amount of acid catalyst used is not especially critical and mayrange from 0.01 molar equivalents to 100 molar equivalents; however, arange of from 0.1 to 10 molar equivalents is generally preferred;however, note that the amount of acid catalyst should be in excess withrespect to the basic nitrogens that may be present in R⁷ of the startingmaterial of compound II or the compound of formula ##STR8## when Z isAlk--NR⁸ R⁹. The time of the reaction may range from 10 minutes to 60hours, with the preferred range being from one-half to 24 hours. Thetemperature of the reaction may range from 20° C. to the boiling pointof the reaction mixture. Preferred temperature ranges include 20° to120° C.

A more detailed description of the prepration of the above intermediatecompounds of formula VII and a description of their subsequentconversion to pyranoindole and thiopyranoindole derivatives of formula Iare disclosed below. For convenience these descriptions are categorizedinto sections according to the group selected for Z for theintermediate.

a. Preparation and Conversion of Intermediates of Formula VII (Z =COOR¹⁹ and Alk¹ --COOR¹⁹)

Intermediates of formula VII (Z = COOR¹⁹ and Alk¹ --COOR¹⁹ in which R¹⁹is hydrogen or lower alkyl and Alk¹ is as defined in the first instance,R⁷ is hydrogen and R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in thefirst instance) are readily obtained by the condensation (II←VI→VII) byusing ketoacids or ketoesters of formula ##STR9## in which R¹ is asdefined in the first instance and Z is COOR¹⁹ or Alk¹ -- COOR¹⁹ asdefined above together with the starting material of formula II (R⁷ =H).

Generally comparable yields of product are obtained in this process wheneither the ketoacid or the corresponding ketoester is used. However, inthe case where it is desired to prepare an acid compound of formulaVII(R⁷ =H) in which Z is Alk¹ COOR¹⁹ wherein Alk¹ is CR¹⁰ R¹¹ and R¹⁹ ishydrogen (i.e., an acid intermediate of formula VII), it is preferableto first condense the appropriate β-ketoester of formula VI rather thanthe corresponding β-ketoacid and then hydrolyze the resulting esterproduct to give the desired acid compound.

Moreover, in the general practise of this invention it is often moreconvenient to prepare the acid compounds of formula VII(R⁷ =H) by usingthe ketoester instead of the ketoacid in this process and then hydrolyzethe resulting ester product to the desired acid, the reason being simplythat the ketoesters are generally more readily available eithercommercially or by synthesis.

The hydrolysis of compounds of formula VII(R⁷ =H) in which Z is COOR¹⁹or Alk¹ COOR¹⁹ wherein Alk¹ is as defined in the first instance and R¹⁹is lower alkyl, i.e. ester intermediates of formula VII(R⁷ =H), to theircorresponding acids of formula VII (R⁷ = H) is readily effected bytreatment with a suitable alkali, for example, potassium hydroxide orsodium carbonate, in aqueous methanol or aqueous ethanol or by treatmentwith lithium iodide in a suitable organic solvent, for example,collidine, see L. F. Fieser and M. Fieser, "Reagents for OrganicSynthesis", John Wiley and Sons, Inc., New York, 1967, pp. 615- 617.

The α-, β-, γ- and δ -ketoacids and -ketoesters of formula VI are eitherknown, for example, ethyl pyruvate, levulinic acid, ethylα,α-dimethylacetoacetate, and β,β-dimethyllevulic acid, or they areprepared by known methods described in general organic chemistrytextbooks. For example, a comprehensive review on the properties andpreparation of such α-, β-, γ- and δ-ketoacids and -ketoesters may befound in "Rodd's Chemistry of the Carbon Compounds", cited above, Vol.Id, pp. 226- 274.

Thereafter these intermediate acids and esters of formula VII (R⁷ = H)are converted to compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined in the first instance and Y is --Alk--NR⁸ R⁹in which Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is as defined in thefirst instance and R⁸ and R⁹ are as defined in the first instance. Thisconversion is accomplished by amidation, reduction and if desirdN-alkylation of the indolic nitrogen. The order of these steps is notcritical. However, we have found the following sequence of these stepsto be both convenient and practical.

First, when it is desired to prepare the derivatives of the latter groupof compounds of formula I in which R⁷ is H, i.e., N-alkylation of theindolic nitrogen is not desired, either the above acid intermediate orester intermediate may be employed.

In the case where the acid intermediate of formula VII(R⁷ = H) isemployed, said acid is subjected to amidation by treatment with a loweralkyl chloroformate, preferably ethyl chloroformate, in the presence oftriethylamine, affording the corresponding mixed anhydride, which isconverted by treatment with the appropriate amine of formula HNR⁸ R⁹ inwhich R⁸ and R⁹ are as defined in the first instance, for example,ammonia, methylamine or dimethylamine, to yield the corresponding amideof formula VII in which Z is CONR⁸ R⁹ or Alk¹ CONR⁸ R⁹ in which Alk¹, R⁸and R⁹ are as described in the first instance.

Alternatively, the latter amides are also obtained by treating the esterintermediates of formula VII (R⁷ = H) with the appropriate amineaccording to known amidation methods, for example, see A. L. F. Beckwithin "The Chemistry of Amides", J. Zalicky, Ed., Interscience Publishers,New York, 1970, pp. 96- 105.

Secondly, the amides so obtained are reduced with a suitable complexmetal hydride to yield the desired pyranoindoles and thiopyranoindoles.Examples of suitable complex metal hydrides are lithium aluminumhydride, lithium aluminum hydride-aluminum chloride, aluminumhydride-aluminum chloride, diborane and sodium borohydride-aluminumchloride. Lithium aluminum hydride is preferred.

On the other hand when it is desired to prepare the compounds of formulaI of the above group in which R¹, R², R³, R⁴, R⁵, R⁶ and X are asdefined in the first instance, R⁷ is lower alkyl, or lower alkenyl,propargyl, phenyl(lower)alkyl or amino(lower)alkyl and Y is --Alk--N R⁸R⁹ in which Alk is CH₂ or Alk¹ CH₂ wherein Alk¹ is as defined in thefirst instance and R⁸ and R⁹ are as defined in the first instance, theacid or ester intermediate of formula VII (R⁷ = H) are first subjectedto N-alkylation by treatment with a molar excess of the appropriateorganic halide, namely a lower alkyl halide, lower alkenyl halide,propargyl halide, phenyl(lower)alkyl halide or amino(lower)alkyl halide,respectively, in an inert solvent in the presence of a proton acceptor.Suitable inert solvents include tetrahydrofuran, benzene, toluene anddimethylformamide. Suitable proton acceptors include sodium hydride,alkali metal carbonate and triethylamine. Preferred conditions foreffecting this N-alkylation include the use of sodium hydride as aproton acceptor and tetrahydrofuran as an inert solvent. Although theoptimum temperature and reaction time will vary depending on thereactants employed, the reaction is generally performed at the boilingpoint of the reaction mixture for a period of 30 minutes to 48 hours.

The lower alkyl halides, lower alkenyl halides, propargyl halide,phenyl(lower)alkyl halides and aminoalkyl(lower)halides employed hereinare either known, for example, ethyl bromide, allyl bromide anddimethylaminoethyl chloride, or they are prepared by known methods,usually by the treatment of the corresponding alcohols with ahalogenating agent, for instance, thionyl chloride, see D. J. Collinsand J. J. Hobbs, Aust. J. Chem., 20, 1413 (1967) and R. B. Moffett, J.Org. Chem., 14, 862 (1949).

In this manner, the corresponding N-alkylated derivatives of the aboveacid and ester derivatives of formula VII are obtained. Thereafter thesederivatives are subjected to the amidation and reduction steps accordingto the conditions described hereinabove in this section, to afford thedesired compounds of formula I in which R⁷ is lower alkyl, loweralkenyl, propargyl, phenyl(lower)alkyl, or amino(lower)alkyl.

Although the above sequence of steps for the conversion of the acid andester intermediates of formula VII (R⁷ = H) to the above desiredpyranoindoles is convenient and efficacious, a change in the order ofthe steps whereby the amides of formula VII (R⁷ = H) are treated withthe appropriate organic halide according to the N-alkylation conditionsdescribed above, followed by reduction with a complex metal hydride, asdescribed above, also affords the above desired compounds of formula I,in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkylor amino(lower)alkyl. Treatment as decribed above, of the resultingcorresponding amide derivative in which the indolic nitrogen isalkylated, also affords the above desired compounds of formula I, inwhich R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower) alkylor amino(lower)alkyl.

Furthermore, another change in the order of the steps for preparing thelatter compounds of formula I is realized by N-alkylation, as describedabove, of the corresponding compounds of formula I in which R⁷ ishydrogen, described above. In this case when the starting materialemployed is a pyranoindole or thiopyranoindole of formula I in which Yis --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ CH₂ where Alk¹ is asdefined in the first instance and R⁸ is hydrogen and R⁹ is hydrogen orlower alkyl, i.e., a primary or secondary amine function is present inthe molecule in addition to the indolic nitrogen, it is expedient to useonly one molar equivalent of the appropriate organic halide to avoidalkylation of the primary or secondary amine if so desired.

Another aspect of the present intermediates of formula VII relates totheir conversion to compounds of formula I in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷ and X are as described in the first instance and Y is --Alk--NR⁸R⁹ in which Alk is CH₂ or Alk¹ CH₂ wherein Alk¹ is as defined in thefirst instance and R⁸ is hydrogen and R⁹ is lower alkyl, i.e. secondaryamines. When it is desired to prepare the latter compounds amodification involving the protection of the secondary amine with abenzyl group or other suitable protecting group, see J. F. McOmie, citedabove is especially convenient. For example, the aforementioned acid orester intermediate of formula VII is reacted with an amine of formulaHNR⁸ R⁹ in which R⁸ is benzyl and R⁹ is lower alkyl according to theamidation step described above. The resulting amide is N-alkylated onthe indolic nitrogen, if desired, and then reduced with a complex metalhydride according to the above procedures. Thereafter the benzyl groupis removed by hydrogenolysis in the presence of a catalyst, preferably10% palladium on carbon, to afford the desired secondary amine compoundsof formula I.

Still another modification relates to a more general reduction of theabove amides of formula VII in which Z is CONR⁸ R⁹ or Alk¹ --CONR⁸ R⁹wherein Alk¹, R⁸ and R⁹ are as defined in the first instance. In otherwords this modification is applicable to the reduction of tertiary,secondary and primary amides, described herein, and is a preferredmodification for the reduction of the latter two. In practising thismodification, the aforementioned amide of formula VII is treated withtriethyloxonium fluoroborate or dimethyl sulfate, see H. Bredereck, etal., Chem. Ber., 98, 2754 (1965), in an inert solvent, for example,methylene dichloride, whereby the corresponding iminoether fluoroborateor methyl sulfate salt is obtained, respectively. Subsequent reductionof the salt thus obtained with a complex metal hydride, similar to thereduction described previously for the amides, yields the correspondingcompounds of formula I. Alternatively, the above fluoroborate or methylsulfate salt derived from a secondary or primary amide is decomposed bybase treatment, for example, with 10% sodium hydroxide or triethylamine,to give the corresponding iminoether which is then reduced in a likemanner to the desired compound of formula I.

When applying the aforementioned steps in the preparation of compoundsof formula I in which R⁶ is hydroxy or lower alkanoyloxy, it ispreferable to use corresponding intermediates in which R⁶ is benzyloxyfollowed by the appropriate transformations as noted previously to yieldthe desired-compounds of formula I.

b. Preparation and Conversion of Intermediates of Formula VII (Z ═ CONR⁸R⁹ and Alk¹ --CONR⁸ R⁹).

The intermediates of formula VII in which R⁷ is hydrogen and Z is CONR⁸R⁹ and Alk¹ --CONR⁸ R⁹ wherein R⁸, R⁹ and Alk¹ are as defined in thefirst instance, described in the previous section, are also obtaineddirectly by utilizing the appropriate starting materials of formula IIand α-, β, γ- or δ-ketoamides of formula ##STR10## in which R¹ is asdefined above and Z is CONR⁸ R⁹ or Alk¹ --CONR⁸ R⁹ in which Alk¹, R⁸ andR⁹ are as defined above. The ketoamides required for this condensationare either known, for example, pyruvamide or α,α-dimethylacetoacetamide,or they are prepared by know methods, for instance, see "Rodd'sChemistry of the Carbon Compounds", cited above, Vol. 1d, pp. 226-274.

Thereafter these amides are converted by the reduction process,described above, to the compounds of formula I in which R¹, R², R³, R⁴,R⁵, R⁶, and X are as defined in the first instance, R⁷ is hydrogen and Yis --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is asdefined in the first instance and R⁸ and R⁹ are as defined in the firstinstance.

c. Preparation and Conversion of Intermediates of Formula VII (Z = CH₂OCOR²⁰ and Alk¹ --CH₂ OCOR²⁰)

Intermediates of formula VII in which R⁷ is hydrogen and Z is CH₂ OCOR²⁰and Alk¹ --CH₂ OCOR²⁰ in which Alk¹ and R²⁰ are as defined in the firstinstance, are obtained when a starting material of formula II (R⁷ =H) iscondensed with a ketoalcohol lower alkanoic acid ester of formula R¹COCH₂ OCOR²⁰ or R¹ CO--Alk¹ --CH₂ OCOR²⁰ in which R¹, Alk¹ and R²⁰ areas defined in the first instance in the presence of a suitable acidcatalyst according to the conditions described above for thecondensation (II + VI→VII). The ketoalcohol lower alkanoic acid estersare either known, for xample, acetonyl acetate or 5-acetoxypentan-2-one,ore are prepared by known methods, for instance, see "Rodd's Chemistryof the Carbon Compounds", cited above, Vol. 1d, pp. 49-54.

These intermediates of formula VII may then be utilized for thepreparation of compounds of formula I of this invention in the followingmanner. The intermediate is hydrolyzed with an aqueous alcoholicsolution of a suitable alkali, for example, sodium hydroxide in aqueousmethanol to afford the corresponding primary alcohol. The primaryalcohol is then oxidized to the corresponding aldehyde. Although avariety of methods are known for the oxidation of a primary alcohol toits corresponding aldehyde, see for example, "Rodd's Chemistry of theCarbon Compounds", cited above, Vol. 1c, pp. 4- 10, we have found thatthe method of K. E. Pfitzner and J. G. Moffat, J. Am. Chem. Soc., 87,5670 (1965), using N,N-dicyclohexylcarbodiimide and dimethyl sulfoxidein the presence of a suitable acid, for example, trifluoroacetic acid,is both efficacious and convenient. Thereafter the aldehyde is reactedwith an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined inthe first instance according to the method of K. N. Campbell, et al., J.Amer. Chem. Soc., 70, 3868 (1948) in the case when the amine used isammonia or a primary amine or according to the method of N. J. Leonardand J. V. Paukstelis, J. Org. Chem., 28, 1397 (1963) when the amine is asecondary amine to give the corresponding Schiff base or ammonium salt,respectively. The product so obtained is reduced with sodiumborohydride, see E. Schenker, Angew. Chem., 73, 81 (1961), to yieldcompounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are asdefined in the first instance, R⁷ is hydrogen and Y is --Alk--NR⁸ R⁹ inwhich Alk is CH₂ or Alk¹ --CH₂ and R⁸ and R⁹ are as defined in the firstinstance.

Alternatively, the latter compounds of formula I are obtained byconverting the above corresponding alcohol to a reactive intermediatesuch as the corresponding halide, mesylate or tosylate, which are thenreacted with a two molar excess of an amine of formula HNR⁸ R⁹ in whichR⁸ and R⁹ are as defined in the first instance. Preferably this reactionis performed in a suitable inert solvent, for example, tetrahydrofuran,at the boiling point of the reaction mixture for a period of eight to 24hours. In connection with alkylations of amines of formula HNR⁸ R⁹ inwhich R⁸ is hydrogen and R⁹ is lower alkyl as disclosed herein, it isgenerally preferable to perform the alkylation with the correspondingN-benzyl derivative of said amine, i.e., an amine of formula HNR⁸ R⁹ inwhich R⁸ is benzyl and R⁹ is lower alkyl. Thereafter, when allappropriate transformation have been performed, the N-benzyl group isremoved by hydrogenolysis with a catalyst, preferably 10% palladium oncarbon, to give the desired compounds of formula I.

Thereafter, and if desired, these latter compounds of formula I areconverted to their corresponding derivatives in which R⁷ is lower alkyl,lower alkenyl, propargyl phenyl(lower) alkyl or amino(lower)alkyl byN-alkylation with one molar equivalent of the appropriate organic halidein the manner described for the N-alkylation in section (a).

Alternatively, the above aldehyde is oxidized with a suiable oxidizingagent to yield the corresponding acid intermediates of formula VII (R⁷ =H) described in section (a). Although a variety of suiable oxidizingagents may be used for this purpose, for example, silver oxide, alkalinepermanganate, hydrogen peroxide, we prefer to use silver oxide accordingto the method of M. Delepine and P. Bonnet, Compt. rend., 149, 39(1909).

Again alternatively, the above aldehyde is converted to its oxime whichon reduction with a complex metal hydride yields the correspondingprimary amine of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are asdefined in the first instance, R⁷ is hydrogen and Y is --Alk--NR⁸ R⁹ inwhich Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is as defined in the firstinstance and R⁸ and R⁹ are hydrogen.

If desired these latter priary amine compounds of formula I may beN-alkylated on the indolic nitrogen in the manner described above with amolar equivalent of the appropriate organic halide to give thecorresponding compounds of formula I in which R⁷ is lower alkyl, loweralkenyl, propargyl, phenyl(lower)alkyl or Alk--NR⁸ R⁹ wherein Alk, R⁸and R⁹ are as defined in the first instance.

In turn these latter compounds of formula I may be further N-alkylatedon the nitrogen of the primary amine with the appropriate lower alkylhalide to the corresponding compounds of formula I in which Y is--Alk--NR⁸ R⁹ wherein Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is asdefined in the first instance and R⁸ is hydrogen or lower alkyl and R⁹is lower alkyl (i.e. secondary or tertiary amines with respect to Y). Inthis case depending on the particular derivative desired theN-alkylation is effected with one or two moles of the alkyl halide togive respectively the secondary (R⁸ = H and R⁹ = lower alkyl withrespect to Y) or tertiary amine (R⁸ = R⁹ = lower alkyl with respect toY). On the other hand the N-alkylation may be effected in two stepsintroducing a different alkyl group each time to afford thecorresponding tertiary amine in which R⁸ and R⁹ are different loweralkyls with respect to Y.

When it is desired to prepare the above tertiary amine compounds inwhich R⁸ or R⁹ are either or both methyl, an alternative alkylationmethod comprises reacting the appropriate corresponding primary orsecondary amine with an aqueous mixture of a substantial excess offormaldehyde and formic acid according to the conditions of theEschweiler-Clarke reaction, see M. L. Moore, Organic Reactions, 5, 301(1949), whereby N-methylation is effected.

Another N-alkylation method which is applied to the above primary andsecondary amines involves acylation with a lower alkanoic anhydride oracid halide and subsequent reduction of the resulting amide.

Furthermore, the above primary amines are used to prepare compounds offormula I in which Y is --Alk--NR⁸ R⁹ wherein Alk is CH₂ or Alk¹ --CH₂and R⁸ and R⁹ together with the nitrogen atom to which they are joinedform a heterocyclic amine radical as defined in the first instance. Whenused in this manner the primary amines are subjected to knownN-alkylation methods, for example, see method J in Moffett, cited above,with the appropriate α,ω-dibromides, or α,ω-dibromides, for example,tetramethylene dibromide, pentamethylene dibromidebis(2-chloroethyl)ether, bis(2-chloroethyl)benzylamine followed byhydrogenation in the presence of 10% palladium on carbon to remove theprotecting benzyl group, a bis(2-chloroethyl)lower alkylamine or abis(2-chloroethyl)-N-[hydroxy(lower)alkyl]amine, to give thecorresponding, desired compound of formula I wherein Y is anamino(lower)alkyl in which the amino portion thereof is pyrrolidino,piperidino, morpholino, piperazino, 4-(lower)alkyl-1-piperazinyl or4-[hydroxy(lower)alkyl]-1-piperazinyl, respectively.

If during the above N-alkylations it is desired to protect primary orsecondary amine functions that are present in the R⁷ portion ofcompounds of formula I, such protection may be afforded by the use ofappropriate protecting groups, for example, a benzyl group; see also, J.F. W. McOmie in "Advances in Organic Chemistry", Vol. 3, R. A. Raphael,et al., Ed., Interscience Publishers, New York, 1963, pp. 191-294.

d. Preparation and Conversion of Intermediates of Formula VII (Z = Alk²--L).

Intermediates of formula VII in which R⁷ is hydrogen and Z is Alk² --Lwherein Alk² and L are as defined in the first instance, are obtainedwhen a starting material of formula II (R⁷ =H) is condensed with a β,γ-or δ-haloketone of formula R¹ CO--Alk² --L in which R¹, Alk² and L aredefined in the first instance in the presence of a suiable acid catalystaccording to the conditions described above for the condensation (II +VI→VII). The haloketones are either known, for example,4-chlorobutan-2-one, or they are prepared by known methods, forinstance, see "Rodd's Chemistry of Carbon Compounds", cited above, Vol.1 c, pp. 70-71 and "Methoden der Organischen Chemie", Houben-Weyl, E.Muller, Ed., Vol. V/3, Georg Thieme Verlag, Stuttgart, 1962, pp.511-1076.

Thereafter these intermediates of formula VII are treated with a twomolar excess of an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are asdefined in the first instance to yield the compounds of formula I inwhich R¹, R², R³, R⁴, R⁵, R⁶ and X are as described in the firstinstance, R⁷ is hydrogen and Y is --Alk--NR⁸ R⁹ in which Alk is Alk² asdefined in the first instance and R⁸ and R⁹ are as defined in the firstinstance. Preferred conditions for this reaction include the use of asuitable inert solvent, for example, tetrahydrofuran, temperaturesranging from 40° - 100° C. or at the boiling point of the reactionmixture and a reaction time of from 8 to 24 hours.

If desired the latter pyranoindoles and thiopyranoindoles may beN-alkylated on the indolic nitrogen with an appropriate lower alkylhalide or aminoalkyl halide according to the method described for theN-alkylation of the pyranoindoles and thiopyranoindoles in section (a).

e. Preparation and Conversion of Intermediates of Formula VII (Z =AlkNR⁸ COR²¹)

Intermediates of formula VII in which R⁷ is hydrogen and Z is AlkNR⁸COR²¹ wherein Alk, R⁸ and R²¹ are as defined in the first instance arereadily obtained by the condensation (II+VI→VII) by using ketoamides offormula ##STR11## in which R¹, Alk, R⁸ and R²¹ are as defined in thefirst instance together with the appropriate starting material offormula II (R⁷ = H).

The ketoamides used herein are either known, for example,formamidoacetone [A. Treibs and W. Sutter, Chem. Ber., 84, 96 (1951)]and see [R. H. Wiley and O. H. Borum, J. Amer. Chem. Soc., 70, 2005(1948)] or they are prepared by known procedures, for example, see"Methoden der Organischen Chemie", cited above, Vol. XI/1, 1957,especially pp. 58-62, 285-289 and 508-509, and F. F. Blicke, OrganicReactions, 1, 303 (1942).

Thereafter, reduction with a complex metal hydride and if desiredN-alkylation of the indolic nitrogen as described in secton (a) convertsthe instant intermediates of formula VII to pyranoindoles of formula Iin which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X are as defined in the firstinstance and Y is AlkNR⁸ R⁹ in which Alk and R⁸ are as defined in thefirst instance and R⁹ is lower alkyl.

f. Preparation and Conversion of Intermediates of Formula VII (Z = Alk-- NO₂)

Intermediates of formula VII in which R⁷ is hydrogen and Z is Alk--NO₂wherein Alk is as defined in the first instance, are obtained by thecondensation (II+VI→VII) when the starting materials of formula II(R⁷ =H) and appropriate α-, β-, γ-, and δ-nitroketones of formula ##STR12##in which R¹ and Alk are as defined in the first instance are employedtherein in the presence of a suitable acid catalyst. In this casetrifluoroacetic acid is the preferred acid catalyst.

The nitroketones used herein are either known, for example,1-nitro-2-propanone, N. Levy and C. W. Scaife, J. Chem. Soc., 1100,(1946) and 5-nitro-2-hexanone, H. Schechter, et al., J. Amer. Chem. Soc.74, 3664 (1952) or they are prepared by known methods, for example, seeLevy, and Scaife, cited above, Shechter, et al. cited above, "Rodd'sChemistry of Carbon Compounds", cited above, Vol. 1c, pp. 71-72 and"Methoden der Organischen Chemie", cited above, Vol. X/1, 1971, p. 203.

Thereafter, these intermediates of formula VII are reduced with acomplex metal hydride, preferably lithium aluminum hydride, to affordthe pyranoindoles of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X areas defined in the first instance, Y is hydrogen and Z is --Alk--NR⁸ R⁹in which Alk is defined in the first instance and R⁸ and R⁹ arehydrogen.

If desired the latter compounds may be N-alkylated according to themethods described in section (c) to give the compounds of formula I inwhich R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined in the firstinstance and Y is Alk--NR⁸ R⁹ in which Alk, R⁸ and R⁹ are as defined inthe first instance.

g. Preparation and Conversion of Intermediates of Formula VII (Z = loweralkyl or phenyl(lower) alkyl)

Intermediates of formula VII (Z = lower alkyl or phenyl(lower)alkyl, R⁷is hydrogen and R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the firstinstance) are readily obtained by the condensation (II+VI→VII) by usingthe starting materials of formula II and the ketones of formula##STR13## in which R¹ is as defined in the first instance and Z is loweralkyl or phenyl(lower)alkyl.

The ketones used herein are either available commercially, for example,acetone or phenylacetone, or they are prepared by conventional methods,for example, see P. Karrer, "Organic Chemistry", 2nd. ed., ElsevierPublishing Co., Inc., New York, 1946, pp. 149-169 and V. Migrdichian,"Organic Synthesis", Vol. 1, Reinhold Publishing Corp., New York, 1957,pp. 100-129.

These intermediates of formula VII are converted to the compounds offormula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in thefirst instance, R⁷ is --(Alk)--NR⁸ R⁹ in which Alk, R⁸ and R⁹ are asdefined in the first instance and Y is lower alkyl or phenyl(lower)alkylby N-alkylation of the indolic nitrogen with the appropriateamino(lower)alkyl halide according to the method of N-alkylationdescribed in section (a).

h. Preparation of Compounds of Formula VII (Z = Alk--NR⁸ R⁹) .tbd.Compounds of Formula I (Y = Alk--NR⁸ R⁹)

The above described starting materials of formula II in which R², R³,R⁴, R⁵, R⁶, R⁷ and X¹ are as defined in the first instance are condensedin the presence of an acid catalyst with an aminoketone of formula R¹CO--Alk--NR⁸ R⁹ in which R¹, Alk, R⁸ and R⁹ are as defined in the firstinstance to give directly the pyrano- and thiopyranoindole derivativesof formula I of this invention.

The requisite aminoketones for this reaction are either known, forexample, 1-dimethylamino-3-butanone, 1-methylamino-3-pentanone, see F.F. Blicke, cited above, or they may be prepared by known procedures, forexample, see "Methoden der Organischen Chemie", cited above, Vol. XI/1,1957, pp. 58-62, 285-289 and 508-509.

In practising this present condensation it is generally advantageous toutilize substantially equimolar amounts of the starting material offormula II and the aminoketone in the presence of an acid catalyst. Inthis particular condensation the amount of the aforementioned acidcatalyst to employ ranges generally from about 1.01 to 100 molarequivalents with respect to the amount of aminoketone reactant, a rangeof from 1.05 to 10 molar equivalents being preferred. If more than onebasic nitrogen is present in the reactants, for example, when R⁸ and R⁹together with the nitrogen atom to which they are attached represent apiperazino radical, then additional acid catalyst is added to compensatefor such basic nitrogens. Optionally, one may employ the acid additionsalts of the aforementioned aminoketones and starting materials offormula II if R⁷ is an amino(lower)alkyl radical, for example thehydrochloride or the sulfate salt. In this case the amount of acidcatalyst may range from 0.01 to 100 molar equivalents, preferably 0.1 to10 molar equivalents. Boron trifluoride is a preferred acid catalyst forthe present condensation. The reaction may be performed conveniently andadvantageously without a solvent, although a high boiling solvent, forexample, toluene, o-xylene or isobutyl ether, amy be used. When thesolvent is omitted, it is desirable to heat the reactants to a melt andstir the melt in an inert atmosphere, for example, nitrogen or helium.Reaction time and temperature depends on the particular reactantsemployed and may be varied. The most convenient reaction time is from1/2 to 48 hours, preferably 1/2 to 4 hours, and reaction temperaturesfrom 20° to 200° C, preferably 60° to 140° C. The reaction in eachindividual case is performed preferably at the lowest temperature atwhich the reaction proceeds smoothly and expeditiously with a minimum ofdecomposition.

In the case where the starting material is one of formula II in which Yis --S--SO₃ Na or --S--SO₃ K, it is preferable to have at least oneequivalent of water present in the reaction mixture. This water may beadded directly to the reaction or it may be included as part of the acidcatalyst. Examples of the latter instance would be whenp-toluenesulfonic acid containing water of crystallization orconcentrated hydrochloric acid are employed as the acid catalyst.

With reference to the preparation of the pyranoindole andthiopyranoindole derivatives of formula Ia, the replacement of thestarting material of formula II in any of the aforementioned processes(a) to (g) with the starting material of formula IIa, ##STR14## in whichR², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance and X¹ isas defined in the first instance, gives the corresponding intermediateof formula VIIa, ##STR15## in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Zare as defined hereinbefore. In the case where Z of said intermediate isAlk--NR⁸ R⁹, the intermediate is the pyranoindole or thiopyranoindole offormula Ia. In the case where Z of said intermediate is other than--Alk--NR⁸ R⁹, the intermediate is transformed to the correspondingpyranoindole or thiopyranoindole of formula Ia by the application ofsteps described hereinbefore for effecting the correspondingtransformation of intermediates of formula VII to the compounds offormula I.

In other words the treatment of the starting material of formula IIawith a comound of formula ##STR16## in which R¹ and Z are as defined inthe first instance according to the conditions of the condensation (II +VI → VII), described hereinbefore, gives the corresponding intermediateof formula VIIa, the latter compound being the corresponding compound offormula Ia or an intermediate therefor.

The requisite starting material of formula IIa in which X¹ is hydroxyand R², R³, R⁴, R⁵, R⁶, and R⁷ is hydrogen is obtained by treating2-(2-indolyl)ethyl tosylate, described by T. Sakan, Tetrahedron Letters,4925 (1968) with 10% sodium hydroxide solution. Optionally, the lattertosylate may be used in the condensation reaction in place of thestarting material of formula IIa in which X¹ is hydroxy and R⁷ ishydrogen. The requisite starting material of formula IIa in which X¹ ishydroxy and R⁷ is defined in the first instance other than hydrogen isobtained by reacting the appropriately substituted indole, for example,N-methylindole, or N-ethylindole, with ethylene oxide or anappropriately substituted ethylene oxide according to the precedure ofJulia, et al., cited above. The requisite starting material of formulaIIa in which X¹ is mercapto, --S--SO₃ --Na or --S--SO₃ --K, are preparedfrom the above corresponding compounds of formula IIa in which X¹ ishydroxy according to the procedure described previously for the similartransformation of starting materials of formula II (X¹ = hydroxy) tostarting materials of formula II (X¹ = mercapto --S--SO₃ Na or --S--SO₃--K).

Finally, it is the intention to cover all changes and modifications ofthe embodiment of the invention herein chosen for the purpose ofdisclosure which are within the scope and spirit of this invention. Suchchanges and modification include those variations which depend on wellknown interconversions of amines, amides, acids and esters oralternation of the order of the steps in the processes disclosed herein.

For example, the act of subjecting the corresponding derivative of thestarting material of formula II or IIa in which the indolic nitrogen isalkylated with a lower alkyl, lower alkenyl, propargyl,phenyl(lower)alkyl or amino(lower)alkyl, to condensation with anappropriate compound of formula VI according to the conditions of thekey reaction taught in this present disclosure to yield thecorresponding intermediate compound of formula VII or VIIa in which theindolic nitrogen is so alkylated would not depart from the scope orspirit of this invention.

More specifically exemplified, the compounds of formula I in which R⁷ islower alkyl are prepared conveniently and generally in good yields byusing the starting material of formula II in which R⁷ is lower alkyl andsubjecting the starting material to treatment with the appropriatecompound of formula ##STR17## and subsequent conversions, if necessary,according to the teachings of the present disclosure.

The following examples illustrate further this invention.

EXAMPLE I 1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]indole-1-Acetic Acid(VII: R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Z = CH₂ COOH)

Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of thestarting material of formula II, tryptophol (10.0 g., 0.06 moles), in200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonicacid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate(Molecular Sieves No. 4) are added. The mixture is subjected to refluxfor 30 minutes, 600 mg. more of p-toluenesulfonic acid is added andrefluxing continued for 21/2 hours. The molecular sieves are collectedand the benzene solution washed successively with 5% sodium bicarbonateand water, dried over sodium sulfate, and evaporated under reducedpressure to dryness affording an oil. The oil is subjected tochromatography on silica gel. Elution with 5% ether in benzene yieldsthe ester, 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acidethyl ester, as an oil, ν_(max) ^(CHCl).spsb.3 1715 cm⁻¹.

Hydrolysis of this ester to the title compound is effected as follows:The ester is dissolved in 230 ml. of methanol. To this is added 10 g. ofKOH in 30 ml. of H₂ O and the solution is allowed to stand at roomtemperature overnight. The methanol is evaporated, water added and thesolution washed with benzene. The aqueous phase is acidified with 6NHCl, and extracted with benzene. This organic phase is washed withwater, dried over sodium sulfate and evaporated to dryness to give anoil, which is crystallized from benzen containing a trace of petroleumether to afford the title compound, m.p. 150° - 152° C., ν_(max)^(CHCl).spsb.3 3325 and 1705 cm⁻¹.

An equivalent amount of methyl acetoacetate may replace ethylacetoacetate in the procedure of this Example. In this case,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-acetic acid methyl ester,m.p. 87° - 90° C. after recrystallization from benzene-hexane, isobtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethylacetoacetate in the procedure of this Example. In this case,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid propylester is obtained as the ester.

EXAMPLE 2 1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-1-PropionicAcid (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Z = CH₂CH₂ COOH)

A mixture of the starting material of formula II, tryptophol (500 mg.),levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphoruspentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirredmagnetically at room temperature for 15 minutes and then at 70° C. for11/2 hr. The reaction mixture is filtered. The filtrate is washed threetimes with 5N NaOH; the combined aqueous phase is washed twice withether and then rendered acidic with cold 50% HCl. The aqueous phase isextracted with chloroform. The chloroform extract is dried (Na₂ SO₄) andevaporated to dryness. The residue is crystallized from ethylacetate-petroleum ether to afford the title compound, m.p. 104° - 110°C., nmr (CDCl₃) δ1.47 (3H), 2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (1H),9.60 (1H).

The above title compound is also obtained by following the procedure ofExample 1 but replacing ethyl acetoacetate with an equivalent amount ofethyl levulinate. In this case1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid ethylester, m.p. 116° - 118° C., ν_(max) ^(CHCl).sbsp.3 1716 cm⁻¹, aftercrystallization from benzene-petroleum ether, is obtained as the esterprior to hydrolysis.

EXAMPLE 3 1-Methyl-1,3,4,9-Tetrahydrothiopyrano[3,4-b]Indole-1-AceticAcid (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = S and Z = CH₂COOH)

Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50ml. of benzene and the solution heated for 30 min. (bath temperature70° - 80° C.). p-Toluenesulfonic acid (0.15 g.) is added and thereaction mixture is subjected to reflux and stirring for 12 hours. Waterformed in the reaction mixture during this period is collected by awater separator. After cooling the benzene solution is washed with 10%solution of sodium bicarbonate, water, saturated brine and dried oversodium sulfate. Evaporation of the benzene solution yields the ester,1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methylester is a semi-solid, ν_(max) ^(CHCl).sbsp.3 1715 cm⁻¹.

This ester is then treated with aqueous alcoholic KOH in the mannerdescribed for the esters in Examples 1 and 2 to afford the titlecompound, m.p. 147° - 149° C., nmr (CDCl₃) δ1.86 (S, 3H), 3.06, 8.12(6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), afterrecrystallization from benzene-hexane.

The procedure of Examples 1, or 3 are followed to prepare othercompounds of formula VII in which R¹, R², R³, R⁴, R⁵, R⁶ and X are asdefined in the first instance, R⁷ is hydrogen and Z is COOR¹⁹ or Alk¹--COOR¹⁹ wherein R¹⁹ and Alk¹ are as defined in the first instance.Examples of such compounds of formula VII are listed in Tables I and II.In each of these examples an equivalent amount of the starting materialof formula II listed therein is used instead of the starting material offormula II described in the procedures of Examples 1 and 3. Note that ineach of these examples the ester obtained prior to hydrolysis is acorresponding ester compound of formula VII.

Similarly, the procedure of Example 2 is used to prepare the productslisted in Tables I and II. In this case an equivalent amount of thestarting material of formula II, listed therein, is used instead of thestarting material of formula II described in Example 2 and an equivalentamount of the corresponding ketoacid of formula VI is used instead ofthe ketoester of formula VI listed therein.

                                      TABLE I                                     __________________________________________________________________________                                                      PRODUCT: [(PREFIX                                       KETOESTER OF          LISTED BELOW)-1,3,                                      FORMULA VI            4,9-TETRAHYDRO-              STARTING MATERIAL OF FORMULA II                                                                           ##STR18##            PYRANO-[3,4-b]IN-                                                             DOLE-1-(SUFFIX LISTED                                                         BELOW)]                     __________________________________________________________________________    Ex. R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                             X R.sup.1                                                                             Alk.sup.1CO  R.sup.19                                                                         PREFIX//SUFFIX              __________________________________________________________________________    4   H   H   H   H   H     O CH.sub.3                                                                            CO           C.sub.2 H.sub.5                                                                  1-methyl//carboxylic                                                          acid                        5   CH.sub.3                                                                          H   H   H   H     O C.sub.2 H.sub.5                                                                     CO           C.sub.2 H.sub.5                                                                  1-ethyl-3-methyl//                                                            carboxylic acid             6   n-C.sub.3 H.sub.7                                                                 H   H   H   5-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CO           CH.sub.3                                                                         1,3-diisopropyl-6-                                                            methyl//carboxylic                                                            acid                        7   CH.sub.3                                                                          CH.sub.3                                                                          H   H   5-OH  O CH.sub.3                                                                            CO           CH.sub.3                                                                         1,3,3-trimethyl-6-                                                            hydroxy//carboxylic                                                           acid                        8   H   H   H   H   7-C.sub.2 H.sub.5                                                                   O n-C.sub.3 H.sub.7                                                                   CO           CH.sub.3                                                                         8-ethyl-1-propyl//                                                            carboxylic acid             9   H   H   i-C.sub.3 H.sub.7                                                                 H   H     O                                                                                ##STR19##                                                                          CO           CH.sub.3                                                                          1-cyclopropyl-4-isopro-                                                       pyl//carboxylic acid       10  CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H     O                                                                                ##STR20##                                                                          CO           CH.sub.3                                                                         1-cyclopentyl-4,4-                                                            diethyl-3,3-dimethyl//                                                        carboxylic acid             11  H   H   CH.sub.3                                                                          H   H     O CH.sub.3                                                                            CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1,4-dimethyl//acetic                                                          acid                        12  H   H   H   H   H     O C.sub.2 H.sub.5                                                                     CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1-ethyl//acetic acid,                                                         m.p. 137 - 140°                                                        C.                          13  H   H   H   H   H     O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1-propyl//acetic acid,                                                        m.p. 148 - 151°                                                        C.                          14  H   H   H   H   H     O i-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1-isopropyl//acetic                                                           acid, m.p. 150 -                                                              152° C.              15  CH.sub.3                                                                          H   H   H   H     O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  3-methyl-1-propyl//                                                           acetic acid;                                                                  m.p. 75 - 80°                                                          C.                                                                            (Isomer A), m.p. 146                                                          148° C. (Isomer                                                        B).                         16  CH.sub.3                                                                          H   C.sub.2 H.sub.5                                                                   CH.sub.3                                                                          H     O C.sub.2 H.sub.5                                                                     CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1,4-diethyl-3-methyl//                                                        acetic acid,                17  H   H   H   H   H     O CH.sub.3                                                                            CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                  α,1-dimethyl//acet                                                      ic                                                                            acid; m.p. 154 -                                                              156° C.                                                                (Isomer A), m.p. 163-                                                         165° C. (Isomer                                                        B).                         18  H   H   H   H   H     O                                                                                ##STR21##                                                                          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.al                                                      pha.- dimethyl//acetic                                                        acid                        19  H   H   H   H   H     O t-C.sub.4 H.sub.9                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1-t-butyl//acetic acid                                                        m.p. 210 - 212°                                                        C.                          20  H   H   H   H   H     O n-C.sub.4 H.sub.9                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1-butyl//acetic acid,                                                         m.p. 124 - 127°                                                        C.                          21  H   H   H   H   7-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  8-methyl-1-propyl//                                                           acetic acid m.p. 127 -                                                        128° C.              22  H   H   H   H   5-Br  O C.sub.2 H.sub.5                                                                     CH.sub.2 CO  C.sub.2 H.sub.5                                                                  6-bromo-1-ethyl//                                                             acetic acid m.p.                                                              182 - 184° C.        23  H   H   H   H   5-OCH.sub.3                                                                         O CH.sub.3                                                                            CH.sub.2 CO  CH.sub.3                                                                         6-methoxy-1-methyl//                                                          acetic acid, m.p.                                                             142 - 143° C.        24  H   H   H   H   5-OCOCH.sub.3                                                                       O CH.sub.3                                                                            CH.sub.2 CO  C.sub.2 H.sub.5                                                                  6-acetoxy-1-methyl//                                                          acetic acid, m.p.                                                             142 - 143° C.        25  H   H   H   H   5-benzyl-                                                                           O CH.sub. 3                                                                           CH.sub.2 CO  C.sub.2 H.sub.5                                                                  6-benzyloxy-1-methyl//                          oxy                           acetic acid, m.p.                                                             163.5° C.            26  H   H   H   H   4-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  5-methyl-1-propyl//                                                           acetic acid, m.p.                                                             177 - 178° C.        27  H   H   H   H   6-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  7-methyl-1-propyl//                                                           acetic acid, m.p.                                                             157 - 158° C.        28  H   H   H   H   5-NO.sub.2                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  6-nitro-1-propyl//                                                            acetic acid, m.p.                                                             119 - 120° C.        29  H   H   CH.sub.3                                                                          CH.sub.3                                                                          H     O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                  4,4-dimethyl-1-                                                               propyl//acetic acid,                                                          m.p. 184 - 185°                                                        C.                          30  CH.sub.3                                                                          CH.sub.3                                                                          H   H   5-OC.sub.2 H.sub.5                                                                  O                                                                                ##STR22##                                                                          CH(C.sub.2 H.sub.5)CO                                                                      C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.a                                                      lpha.- diethyl-3,3-dimet                                                      hyl- 6-ethoxy//acetic                                                         acid                        31  CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-C.sub.2 H.sub.5                                                                   O                                                                                ##STR23##                                                                          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.al                                                      pha.,3,3-  tetramethyl-4                                                      ,4,7- triethyl//acetic                                                        acid                        32  CH.sub.3                                                                          H   n-C.sub.3 H.sub.7                                                                 n-C.sub.3 H.sub.7                                                                 4-n-C.sub.3 H.sub.7                                                                 O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                  α,3-dimethyl-1-eth                                                      yl-                                                                           4,4,5-tripropyl//                                                             acetic acid                 33  H   H   H   H   H     O n-C.sub.3 H.sub.7                                                                   C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                  α,α-dimethyl                                                      -1-                                                                           propyl//acetic acid         34  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   4-C.sub.2 H.sub.5                                                                   O t-C.sub.4 H.sub.9                                                                   C(i-C.sub.3 H.sub.7).sub.2 CO                                                              C.sub.2 H.sub.5                                                                  1-t-butyl-α,.alpha                                                      .-                                                                            diisopropyl-3,3,4,4,5-                                                        pentaethyl//acetic                                                            acid                        35  H   H   H   H   4-I   O i-C.sub.3 H.sub.7                                                                   CH.sub.2 CH.sub.2 CO                                                                       C.sub.2 H.sub.5                                                                  5-iodo-1-isopropyl//                                                          propionic acid              36  CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           ##STR24##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CH(CH.sub.3)CO                                                                    C.sub.2 H.sub.5                                                                  8-acetoxy-1-ethyl-                                                            α,3,3,4,4-                                                              pentamethyl//                                                                 propionic acid              37  H   H   H   H   6-OH  O n-C.sub.3 H.sub.7                                                                   CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                                          C.sub.2 H.sub.5                                                                  β,β-diethyl-7-                                                      hydroxy                                                                       1-propyl//propionic                                                           acid                        38  CH.sub.3                                                                          H   H   H   7-NO.sub.2                                                                          O                                                                                ##STR25##                                                                          CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                           C.sub.2 H.sub.5                                                                  1-cyclobutyl-3-methyl-                                                        8-nitro-α-propyl//                                                       propionic acid             39  H   H   CH.sub.3                                                                          H   5-CH.sub.3                                                                          O                                                                                ##STR26##                                                                          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                        C.sub.2 H.sub.5                                                                   ##STR27##                  40  CH.sub.3                                                                          H   H   H   H     O CH.sub.3                                                                            CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                        C.sub.2 H.sub.5                                                                  1,3-dimethyl-α,.al                                                      pha.-                                                                         dipropyl//propionic                                                           acid                        41  CH.sub.3                                                                          H   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H     O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                           CH.sub.3                                                                         α,α,β,3                                                      -tetramethyl-                                                                 1,4,4-triethyl//                                                              propionic acid              42  H   H   CH.sub.3                                                                          CH.sub.3                                                                          H     O C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 CO                                                              CH.sub.3                                                                         1-ethyl-β,β,4,                                                      4-                                                                            tetramethyl//propionic                                                        acid                        43  H   H   n-C.sub.3 H.sub.7                                                                 H                                                                                  ##STR28##                                                                          O                                                                                ##STR29##                                                                          C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                            H.sub.5)CO   CH.sub.3                                                                         1-cyclopentyl-5-                                                              propionoxy-4-propyl-                                                          α,β,β-tr                                                      iethyl// propionic                                                            acid                        44  n-C.sub.3 H.sub.7                                                                 H   H   H   4-OCH.sub.3                                                                         O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CH(CH.sub.3)CO                                                                    C.sub.2 H.sub.5                                                                  1,3-dipropyl-5-methoxy                                                        α-methyl//propioni                                                      c                                                                             acid                        45  C.sub.2 H.sub.5                                                                   H   H   H   5-NO.sub.2                                                                          O CH.sub.3                                                                            C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                            H.sub.5).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                  1-methyl-6-nitro-α                                                      ,α,-                                                                    β,β,3-pentaeth                                                      yl//                                                                          propionic acid              46  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H   H   4-C.sub.2 H.sub.5                                                                   O n-C.sub.3 H.sub.7                                                                   CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                           CH.sub.3                                                                         β,1-dipropyl-3,3,5-                                                      N                                                                             triethyl//propionic                                                           acid                        47  H   H   H   H   6-OC.sub.2 H.sub.5                                                                  O                                                                                ##STR30##                                                                          CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)CO                                      O            C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.b                                                      eta.- diethyl-7-ethoxy//                                                       propionic acid             48  H   H   H   H   H     O CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                  1-methyl//butyric acid                                                        m.p. 132 - 135°                                                        C.                          49  CH.sub.3                                                                          H   H   H   H     O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                           C.sub.2 H.sub.5                                                                  γ,3-dimethyl-1-eth                                                      yl//                                                                          butyric acid                50  CH.sub.3                                                                          CH.sub.3                                                                          H   H   H     O n-C.sub.3 H.sub.7                                                                   C(C.sub.2 H.sub.5).sub.2 CH.sub.2                                             CH.sub.2 CO  C.sub.2 H.sub.5                                                                  γ,γ-diethyl-                                                      3,3-                                                                          dimethyl-1-propyl//                                                           butyric acid                51  CH.sub.3                                                                          CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                 H   H     O                                                                                ##STR31##                                                                          C(n-C.sub.3 H.sub.7).sub.2 CH(n-C.sub.3                                       H.sub.7)CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   ##STR32##                  52  H   H   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   6-Cl  O CH.sub.3                                                                             ##STR33##   C.sub.2 H.sub.5                                                                  7-chloro-α,β,                                                      β,γ,γ,4                                                      ,- heptaethyl-1-methyl//                                                       butyric acid               53  H   H   CH.sub.3                                                                          H   4-CH.sub.3                                                                          O C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 CO                                                              C.sub.2 H.sub.5                                                                  1-ethyl-α,α,                                                      β,β,γ,.g                                                      amma.,4-                                                                      4,5-octamethyl//                                                              butyric acid                54  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H                                                                                  ##STR34##                                                                          O n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)[C(C.sub.2 H.sub.5)].                                      sub.2 CO     C.sub.2 H.sub.5                                                                  6-acetoxy-α,.alpha                                                      .,β,β,γ,                                                      3, 3,4-octaethyl-1-propy                                                      l- butyric acid             55  H   H   CH.sub.3                                                                          CH.sub.3                                                                          7-OCH.sub.3                                                                         O                                                                                ##STR35##                                                                          CH.sub.2 [C(CH.sub.3).sub.3 ].sub.2                                                        C.sub.2 H.sub.5                                                                  1-cyclobutyl-α,.al                                                      pha.,β,β,                                                           4,4-hexamethyl-8-                                                             methoxy//butyric acid       56  H   H   H   H   4-Br  O                                                                                ##STR36##                                                                          CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                        CO           C.sub.2 H.sub.5                                                                  5-bromo-1-cyclopentyl-                                                        α,α,β-t                                                      rimethyl// butyric                                                            acid                        57  CH.sub.3                                                                          CH.sub.3                                                                          H   H   4-n-C.sub.3 H.sub.7                                                                 O                                                                                ##STR37##                                                                          CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub                                      .2 CO        C.sub.2 H.sub.5                                                                   ##STR38##                  58  H   H   H   H   7-C.sub.2 H.sub.5                                                                   O C.sub.2 H.sub.5                                                                     CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                           C.sub.2 H.sub.5                                                                  1,8-diethyl-α-meth                                                      yl//                                                                          butyric acid                59  CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                          H   5-F   O n-C.sub.4 H.sub.9                                                                   [CH(CH.sub.3)].sub.3 CO                                                                    C.sub.2 H.sub.5                                                                  1-butyl-6-fluoro-α                                                      ,β,                                                                      γ,3,3,4-hexamethyl                                                      //                                                                            butyric acid                60  CH.sub.3                                                                          CH.sub.3                                                                          H   H   4-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                        H.sub.5)CO   C.sub.2 H.sub.5                                                                  α,γ-diethyl-                                                      1-propyl-                                                                     3,3,5-trimethyl//                                                             butyric acid                61  C.sub.2 H.sub.5                                                                   H   H   H   6-NO.sub.2                                                                          O n-C.sub.4 H.sub.9                                                                   [C(CH.sub.3).sub.2 ].sub.3 CO                                                              C.sub.2 H.sub.5                                                                  1-butyl-3-ethyl-7-                                                            nitro-α,β,.ga                                                      mma.-                                                                         trimethyl//butyric                                                            acid                        62  CH.sub.3                                                                          CH.sub.3                                                                          H   H   4-n-C.sub.3 H.sub.7                                                                 O n-C.sub.3 H.sub.7                                                                   CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                                       C.sub.2 H.sub.5                                                                  α,β-diethyl-3                                                      ,3-                                                                           dimethyl-1,5-dipropyl//                                                       butyric acid                63  H   H   H   H   7-OH  O C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3).s                                      ub.2 CO      C.sub.2 H.sub.5                                                                  1-ethyl-8-hydroxy-                                                            α,α,γ,                                                      γ-tetramethyl//                                                         butyric acid                64  CH.sub.3                                                                          H   CH.sub.3                                                                          H   4-OC.sub.2 H.sub.5                                                                  O C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 CO                                                              C.sub.2 H.sub.5                                                                  5-ethoxy-1-ethyl-α                                                      ,α,-                                                                    β,β,γ,.g                                                      amma.,3,4-                                                                    octomethyl//butyric                                                           acid                        64a H   H   H   H   4-CH.sub.3                                                                          O CH.sub.3                                                                            CH.sub.2 CO  C.sub.2 H.sub.5                                                                  1,5-dimethyl//acetic                                                          acid, m.p. 150 -                                                              152° C.              64b H   H   H   H   4-Cl  O CH.sub.3                                                                            CH.sub.2 CO  CH.sub.3                                                                         5-chloro-1-methyl//                                                           acetic acid, m.p. 183                                                         -                                                                             184° C.              __________________________________________________________________________

                                      table ii                                    __________________________________________________________________________                                ketoester of            Product: [(prefix                                     Formula VI              listed                                                                        below)-1,3,4,9-            Starting Material of Formula II                                                                           ##STR39##              Tetrahydrothiopyrano-                                                         [3,4-b]indole-1-                                                              (suffix listed            __________________________________________________________________________                                                        below)]                   Ex.                                                                              R.sup.2                                                                            R.sup.3                                                                          R.sup.4                                                                            R.sup.5                                                                           R.sup.6                                                                             X R.sup.1                                                                            Alk.sup.1CO     R.sup.19                                                                         Prefix//Suffix            __________________________________________________________________________    65 H    H  H    H   H     S CH.sub.3                                                                           CO              C.sub.2 H.sub.5                                                                  1-methyl//carboxylic                                                          acid                      66 CH.sub.3                                                                           H  H    H   H     S C.sub.2 H.sub.5                                                                    CO              C.sub.2 H.sub.5                                                                  1-ethyl-3-methyl//                                                            carboxylic acid           67 i-C.sub.3 H.sub.7                                                                  H  H    H   5-CH.sub.3                                                                          S i-C.sub.3 H.sub.7                                                                  CO              CH.sub.3                                                                         1,3-diisopropyl-6-                                                            methyl//carboxylic                                                            acid                      68 CH.sub.3                                                                           CH.sub.3                                                                         H    H   5-OH  S CH.sub.3                                                                           CO              CH.sub.3                                                                         1,3,3-trimethyl-6-                                                            hydroxy-1-(1-propyl)//                                                        carboxylic acid           69 H    H  H    H   7-C.sub.2 H.sub.5                                                                   S n-C.sub.3 H.sub.7                                                                  CO              CH.sub.3                                                                         8-ethyl-1-propyl//                                                            carboxylic acid           70 H    H  i-C.sub.3 H.sub.7                                                                  H   H     S                                                                                ##STR40##                                                                         CO              CH.sub.3                                                                         1-cyclopropyl-4-                                                              isopropyl//carboxylic                                                          acid                     71 CH.sub.3                                                                           CH.sub.3                                                                         C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   H     S                                                                                ##STR41##                                                                         CO              CH.sub.3                                                                         1-cyclopentyl-4,4-                                                            diethyl-3,3-dimethyl//                                                          carboxylic acid         72 H    H  CH.sub.3                                                                           H   H     S CH.sub.3                                                                           CH.sub.2 CO     C.sub.2 H.sub.5                                                                  1,4-dimethyl//acetic                                                          acid                      73 H    H  H    H   H     S C.sub.2 H.sub.5                                                                    CH.sub.2 CO     C.sub.2 H.sub.5                                                                  1-ethyl//acetic                                                               acid,                                                                         m.p. 138° C.       74 H    H  H    H   H     S n-C.sub.3 H.sub.7                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  1-propyl//acetic                                                              acid,                                                                         m.p. 127                                                                      - 129° C.          75 H    H  H    H   H     S i-C.sub.3 H.sub.7                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  1-isopropyl//acetic                                                           acid                      76 CH.sub.3                                                                           H  H    H   H     S n-C.sub.3 H.sub.7                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  3-methyl-1-propyl//                                                           acetic acid               77 CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                    CH.sub.3                                                                          H     S C.sub.2 H.sub.5                                                                    CH.sub.2 CO     C.sub.2 H.sub.5                                                                  1,4-diethyl-3-methyl//                                                        A                                                                             acetic acid               78 H    H  H    H   H     S CH.sub.3                                                                           CH(CH.sub.3)CO  C.sub.2 H.sub.5                                                                  α,1-dimethyl//ac                                                        etic                                                                          acid                      79 H    H  H    H   H     S                                                                                ##STR42##                                                                         C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.                                                        alpha.-                                                                       dimethyl//acetic                                                              acid                      80 H    H  H    H   H     S t-C.sub.4 H.sub.9                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  1-t-butyl//acetic                                                             acid                      81 H    H  H    H   H     S n-C.sub.4 H.sub.9                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  1-butyl//acetic acid      82 H    H  H    H   7-CH.sub.3                                                                          S n-C.sub.3 H.sub.7                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  8-methyl-1-propyl//                                                           acetic acid               83 H    H  H    H   5-Br  S n-C.sub.3 H.sub.7                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  6-bromo-1-propyl//                                                            acetic acid               84 H    H  H    H   5-OCH.sub.3                                                                         S CH.sub.3                                                                           CH.sub.2 CO     CH.sub.3                                                                         6-methoxy-1-methyl//                                                          acetic acid               85 H    H  H    H   5-OCOCH.sub.3                                                                       S CH.sub.3                                                                           CH.sub.2 CO     C.sub.2 H.sub.5                                                                  6-acetoxy-1-methyl//                                                          acetic acid               86 H    H  H    H   5-benzyl-                                                                           S CH.sub.3                                                                           CH.sub.2 CO     C.sub.2 H.sub.5                                                                  6-benzyloxy-1-methyl//                                                        T                                             oxy                             acetic acid               87 H    H  H    H   4-CH.sub.3                                                                          S n-C.sub.3 H.sub.7                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  5-methyl-1-propyl//                                                           acetic acid               88 H    H  H    H   6-CH.sub.3                                                                          S n-C.sub.3 H.sub.7                                                                  CH.sub.2 CO     C.sub.2 H.sub.5                                                                  7-methyl-1-propyl//                                                           acetic acid               89 H    H  H    H   7-F   S CH.sub.3                                                                           C(C.sub.2 H.sub.5).sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  α,α-diethy                                                        l-8-fluoro-1-                                                                 methyl//acetic acid       90 CH.sub.3                                                                           CH.sub.3                                                                         H    H   5-Cl  S n-C.sub.3 H.sub.7                                                                  CH(iC.sub.3 H.sub.7)CO                                                                        C.sub.2 H.sub.5                                                                  6-chloro-3,3-dimethyl-                                                        α-isopropyl-1-                                                          propyl//acetic acid       91 CH.sub.3                                                                           CH.sub.3                                                                         H    H   5-OC.sub.2 H.sub.5                                                                  S                                                                                ##STR43##                                                                         CH(C.sub.2 H.sub.5)CO                                                                         C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,                                                        α-                                                                      diethyl-3,3-                                                                  dimethyl-6-ethoxy//                                                           cetic acid                92 CH.sub.3                                                                           CH.sub.3                                                                         C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   6-C.sub.2 H.sub.5                                                                   S                                                                                ##STR44##                                                                         C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.                                                        alpha.,3,3-                                                                   tetramethyl-4,4,7-                                                            triethyl//acetic                                                              acid                      93 CH.sub.3                                                                           H  n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                 4-n-C.sub.3 H.sub.7                                                                 S C.sub.2 H.sub.5                                                                    CH(CH.sub.3)CO  C.sub.2 H.sub.5                                                                  α,3-dimethyl-1-e                                                        thyl-                                                                         4,4,5-tripropyl//                                                             acetic acid               94 H    H  H    H   H     S n-C.sub.3 H.sub.7                                                                  C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                  α,α-dimeth                                                        yl-1-                                                                         propyl//acetic acid       95 C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   4-C.sub.2 H.sub.5                                                                   S t-C.sub.4 H.sub.9                                                                  C(i-C.sub.3 H.sub.7).sub.2 CO                                                                 C.sub.2 H.sub.5                                                                  1-t-butyl-α,.alp                                                        ha.-                                                                          diisopropyl-3,3,4,4-                                                          5-pentaethyl//acetic                                                          acid                      96 H    H  H    H   H     S CH.sub.3                                                                           CH.sub.2 CH.sub.2 CO                                                                          C.sub.2 H.sub.5                                                                  1-methyl//                                                                    propionic acid            97 CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                           ##STR45##                                                                          S C.sub.2 H.sub.5                                                                    CH.sub.2 CH(CH.sub.3)CO                                                                       C.sub.2 H.sub.5                                                                  8-acetoxy-l-ethyl-                                                            α,3,3,4,4-                                                              pentamethyl//                                                                 propionic acid            98 H    H  H    H   6-OH  S n-C.sub.3 H.sub.7                                                                  CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                                             C.sub.2 H.sub.5                                                                  β,β-diethyl-                                                        7-                                                                            hydroxy-1-propyl//                                                            propionic acid            99 CH.sub.3                                                                           H  H    H   7-NO.sub.2                                                                          S                                                                                ##STR46##                                                                         CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                  1-cyclobutyl-3-                                                               methyl-8-nitro-α                                                        -  propyl//propionic                                                          cid                       100                                                                              H    H  CH.sub.3                                                                           H   5-CH.sub.3                                                                          S                                                                                ##STR47##                                                                         C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                           C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,                                                        α,β,β-                                                          4,6-hexamethyl//                                                            propionic acid            101                                                                              CH.sub.3                                                                           H  H    H   H     S CH.sub.3                                                                           CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                           C.sub.2 H.sub.5                                                                  1,3-dimethyl-α,.                                                        alpha.-                                                                       dipropyl//propionic                                                           acid                      102                                                                              CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                    H   S     C.sub.2 H.sub.5                                                                 CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                   CH.sub.3        1,4,4-triethyl-α,.a                                                     lpha.,β-                                                                    3-tetramethyl//                                                               propionic acid            103                                                                              H    H  CH.sub.3                                                                           CH.sub.3                                                                          H     S C.sub.2 H.sub.5                                                                    C(CH.sub.3).sub.2 CH.sub.2 CO                                                                 CH.sub.3                                                                         1-ethyl-β,β,                                                        4,4-                                                                          tetramethyl//                                                                 propionic acid            104                                                                              H    H  n-C.sub.3 H.sub.7                                                                  H                                                                                  ##STR48##                                                                           ##STR49##                                                                      2 H.sub.5).sub.2 C(C.sub.2 H.sub.5)CO                                              CH.sub.3        1-cyclopentyl-5-                                                              propionoxy-4-propyl-                                                          α,β,β-tri                                                     ethyl//  propionic acid      105                                                                              n-C.sub.3 H.sub.7                                                                  H  H    H   4-OCH.sub.3                                                                         S n-C.sub.3 H.sub.7                                                                  CH.sub.2 CH(CH.sub.3)CO                                                                       C.sub.2 H.sub.5                                                                  1,3-dipropyl-5-                                                               methoxy-α-methyl                                                        //                                                                            propionic acid            106                                                                              C.sub.2 H.sub.5                                                                    H  H    H   5-NO.sub.2                                                                          S CH.sub.3                                                                           C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                            H.sub.5).sub.2 CO                                                                             C.sub.2 H.sub.5                                                                  1-methyl-6-nitro-                                                             α,α,β                                                        ,β,3-pentaethyl//                                                        propionic acid            107                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  H    H   4-C.sub.2 H.sub.5                                                                   S n-C.sub.3 H.sub.7                                                                  CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                              CH.sub.3                                                                         β,1-dipropyl-3,3,                                                        5-                                                                            triethyl//propionic                                                           acid                      108                                                                              H    H  H    H   6-OC.sub.2 H.sub.5                                                                  S                                                                                ##STR50##                                                                         CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)CO                                                      C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,                                                        β-                                                                       diethyl-7-ethoxy//                                                            propionic acid            109                                                                              H    H  H    H   H     S CH.sub.3                                                                           CH.sub.2 CH.sub.2 CH.sub.2 CO                                                                 C.sub.2 H.sub.5                                                                  1-methyl//butyric                                                             acid                      110                                                                              CH.sub.3                                                                           H  H    H   H     S C.sub.2 H.sub.5                                                                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                              C.sub.                                                                           γ,3-dimethyl-1-e                                                        thyl//                                                                        butyric acid              111                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H    H   H     S n-C.sub.3 H.sub.7                                                                  C(C.sub.2 H.sub.5).sub.2 CH.sub.2                                             CH.sub.2 CO     C.sub.2 H.sub.5                                                                  γ,γ-diethy                                                        l-3,3-                                                                        dimethyl-1-propyl//                                                           butyric acid              112                                                                              CH.sub.3                                                                           CH.sub.3                                                                         n-C.sub.3 H.sub.7                                                                  H   H     S                                                                                ##STR51##                                                                         C(n-C.sub.3 H.sub.7).sub.2 CH(n-C.sub.3                                       H.sub.7 CH.sub.2 CO                                                                           C.sub.2 H.sub.5                                                                  1-cyclobutyl-3,3-                                                             dimethyl-β,.gamma                                                        .,γ,4-                                                                  tetrapropyl//                                                                 butyric acid              113                                                                              H    H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   6-Cl  S CH.sub.3                                                                           [C(C.sub.2 H.sub.5).sub.2 ].sub.2                                             CH(C.sub.2 H.sub.5)CO                                                                         C.sub.2 H.sub.5                                                                  7-chloro-α,.beta                                                        .,β,γ,.gamm                                                        a.,-                                                                          4,4-heptaethyl-1-                                                             methyl//butyric acid      114                                                                              H    H  CH.sub.3                                                                           H   4-CH.sub.3                                                                          S C.sub.2 H.sub.5                                                                    [C(CH.sub.3).sub.2 ].sub.3 CO                                                                 C.sub.2 H.sub.5                                                                  1-ethyl-α,.alpha                                                        .,β,β,.gamma                                                        .,γ,-                                                                   4,5-octamethyl//                                                              butyric acid              115                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                    H                                                                                  ##STR52##                                                                          S n-C.sub.3 H.sub.7                                                                  n-C.sub. H.sub.7                                                                              CH(C.sub.2 H.sub.5)[C(C.s                                                     ub.2 H.sub.5)].sub.2                                                             6-acetoxy-α,.alp                                                        ha.,β,β,-                                                           γ,3,3,4-octaethy                                                        l-1-  propyl//butyric                                                         acid                      116                                                                              H    H  CH.sub.3                                                                           CH.sub.3                                                                          7-OCH.sub.3                                                                         S                                                                                ##STR53##                                                                         CH.sub.2 [C(CH.sub.3).sub.3 ].sub.2                                                           C.sub.2 H.sub.5                                                                  1-cyclobutyl-α,.                                                        alpha.,β-                                                                β4,4-hexamethyl-8                                                        -   methoxy//butyric                                                          acid                      117                                                                              H    H  H    H   4-Br  S                                                                                ##STR54##                                                                         CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                        CO              C.sub.2 H.sub.5                                                                  5-bromo-1-cyclopentyl                                                          α,α,.beta                                                        .-trimethyl//                                                                 butyric acid              118                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H    H   4-n-CH.sub.3                                                                        S                                                                                ##STR55##                                                                         CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.                                     2 CO            C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,                                                        α-                                                                      diethyl-3,3-dimethyl-                                                          5-propyl//butyric                                                            acid                      119                                                                              H    H  H    H   7-C.sub.2 H.sub.5                                                                   S C.sub.2 H.sub.5                                                                    CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                              C.sub.2 H.sub.5                                                                  1,8-diethyl-α-                                                          methyl//butyric acid      120                                                                              CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                           H   5-F   S n-C.sub.4 H.sub.9                                                                  [CH(CH.sub.3)].sub.3 CO                                                                       C.sub.2 H.sub.5                                                                  1-butyl-6-fluoro-                                                             α,β,γ                                                        ,3,3,4-                                                                       hexamethyl//butyric                                                           acid                      121                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H    H   4-CH.sub.3                                                                          S n-C.sub.3 H.sub.7                                                                  CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                        H.sub.5)CO      C.sub.2 H.sub.5                                                                  α,γ-diethy                                                        l-1-                                                                          propyl-3,3,5-trimethyl                                                        butyric acid              122                                                                              C.sub.2 H.sub.5                                                                    H  H    H   6-NO.sub.2                                                                          S n-C.sub.4 H.sub.9                                                                  [C(CH.sub.3).sub.2 ].sub.3 CO                                                                 C.sub.2 H.sub.5                                                                  1-butyl-3-ethyl-7-                                                            nitro-α,β,)                                                        -                                                                             trimethyl//butyric                                                            acid                      123                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H    H   4-n-C.sub.3 H.sub.7                                                                 S n-C.sub.3 H.sub.7                                                                  CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                                          C.sub.2 H.sub.5                                                                  α,β-diethyl                                                        -                                                                             3,3-dimethyl-1,5-                                                             dipropyl//butyric                                                             acid                      124                                                                              H    H  H    H   7-OH  S C.sub.2 H.sub.5                                                                    C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3).su                                     b.2 CO          C.sub.2 H.sub.5                                                                  1-ethyl-8-hydroxy-                                                            α,α,.gamma                                                        .,γ-tetramethyl                                                         butyric acid              125                                                                              CH.sub.3                                                                           H  CH.sub.3                                                                           H   4-OC.sub.2 H.sub.5                                                                  S C.sub.2 H.sub.5                                                                    [C(CH.sub.3).sub.2 ].sub.3 CO                                                                 C.sub.2 H.sub.5                                                                  5-ethoxy-1-ethyl-                                                             α,α,β                                                        ,β,γ,.gamma                                                        .,3,4-                                                                        octomethyl//butyric                                                           acid                      __________________________________________________________________________

EXAMPLE 126N,N,1-Trimethyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-1-Acetamide [VII;R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Z = CH₂ CON(CH₃)₂ ]

To a stirred solution of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g,0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran(300 ml), cooled to -5° C., is added triethylamine (18.5 g, 0.183 mole),followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture isstirred at -5° C. for 2 hr. This mixture, which now contains the mixedanhydride of the above starting material, is added dropwise to a cooled40% aqueous solution of the amine, dimethylamine (225 ml). The resultingmixture is stirred at room temperature for one-half hour. Most of thetetrahydrofuran is evaporated, and the residue partitioned betweenchloroform and water. The organic phase is washed with water, dried oversodium sulfate, and evaporated under reduced pressure. The residue issubjected to chromatography on silica gel. Elution with 20% ethylacetate in benzene, followed by crystallization of the elute from ethylacetate affords the title compound, m.p. 149° - 151° C., ν_(max)^(CHCl).sbsp.3 3375, 1634 cm⁻¹.

In the same manner but replacing the 40% aqueous solution ofdimethylamine with an equivalent amount of ammonium hydroxide(concentrated), methylamine (30% aqueous solution), n-hexylamine (20%aqueous solution), diethylamine (30% aqueous solution), isopropylamine(40% aqueous solution), ethylamine (70% aqueous solution), pyrrolidine(50% aqueous solution), piperidine, morpholine, N-methylpiperazine,

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 158° -160° C.,

N1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p.138° - 140° C.,

N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,n-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,m.p. 99° C., ν_(max) ^(CHCl).sbsp.3 3350, 1620 cm⁻¹,

N-isopropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,m.p. 151° - 153° C.,

N-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p.152° - 153° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]pyrrolidine,m.p. 119° - 120° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]piperidine,m.p. 148° - 149° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]morpholine,m.p. 141° - 142° C., and

1-methyl-4-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)-acetyl]piperazine,are obtained respectively.

By following the procedure of Example 126 but using as starting materialan equivalent amount of one of the acid compounds of formula VII,described in Examples 2 to 125, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and usingan equivalent amount of an appropriate amine such as ammonia or aprimary or secondary amine described in Example 126, then thecorresponding amide compound of formula VII is obtained. Examples ofsuch amides are listed as products in Tables III, IV, V and VI togetherwith the appropriate starting material and amine used for thepreparation of the amide. In each case the starting material is noted bythe example in which it is prepared.

                                      TABLE III                                   __________________________________________________________________________            NO. OF THE EXAMPLE PRODUCT: [(PREFIX LISTED BELOW)-                          IN WHICH STARTING   1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS         INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED     AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________    127    2            CH.sub.3 NH.sub.2                                                                    N,1-dimethyl//propionamide,                                                   m.p. 149 - 150° C.                          128    2            NH.sub.3                                                                             1-methyl//propionamide                             129    2            (CH.sub.3).sub.2 NH                                                                  N,N,1-trimethyl//propionamide                      130    2            n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-methyl//propionamide                     131    2            (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-methyl//propionamide                 132    4            CH.sub.3 NH.sub.2                                                                    N,1-dimethyl//carboxamide                          133    4            NH.sub.3                                                                             1-methyl//carboxamide, m.p. 188 -                                             189° C.                                     134    4            (CH.sub.3).sub.2 NH                                                                  N,N,1-trimethyl//carboxamide                       135    4            n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-methyl//carboxamide                      136    4            C.sub.2 H.sub.5 NH.sub.2                                                             N-ethyl-1-methyl//carboxamide                      137    5            CH.sub.3 NH.sub.2                                                                    N,3-dimethyl-1-ethyl//carboxamide                  138    9            (CH.sub.3).sub.2 NH                                                                  1-cyclopropyl-N,N-dimethyl-4-iso-                                             propyl//carboxamide                                139    11           (CH.sub.3).sub.2 NH                                                                  N,N,1,4-tetramethyl//acetamide                     140    12           CH.sub.3 NH.sub.2                                                                    1-ethyl-N-methyl//acetamide                        141    12           NH.sub.3                                                                             1-ethyl//acetamide                                 142    12           (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-ethyl//acetamide                    143    12           n-C.sub.16 H.sub.13 NH.sub.2                                                         1-ethyl-N-hexyl//acetamide                         144    12           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N,1-triethyl//acetamide                          145    13           CH.sub.3 NH.sub.2                                                                    N-methyl-1-propyl//acetamide                       146    13           NH.sub.3                                                                             1-propyl//acetamide                                147    13           (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-propyl//acetamide,                                             m.p. 159 - 162° C.                          148    13           n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-propyl//acetamide                        149    13           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-propyl//acetamide                    150    14           CH.sub.3 NH.sub.2                                                                    1-isopropyl-N-methyl//acetamide                    151    14           NH.sub.3                                                                             1-isopropyl//acetamide                             152    14           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-isopropyl//acetamide                 153    15           CH.sub.3 NH.sub.2                                                                    N,3-dimethyl-1-propyl//acetamide                   154    15           (CH.sub.3).sub.2 NH                                                                  1-propyl-N,N,3-trimethyl//                                                    acetamide                                          155    15           n-C.sub.6 H.sub.13 NH.sub.2                                                          n-hexyl-3-methyl-1-propyl//                                                   acetamide                                          156    15           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-3-methyl-1-propyl//                                               acetamide                                          157    17           CH.sub.3 NH.sub.2                                                                    N,α,1-trimethyl//acetamide                   158    17           NH.sub.3                                                                             α,1-dimethyl//acetamide                      159    17           (CH.sub.3).sub.2 NH                                                                  N,N,α,1-tetramethyl//acetamide               160    17           n-C.sub.6 H.sub.13 NH.sub.2                                                          α,1-dimethyl-N-hexyl//acetamide              161    17           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-α,1-dimethyl//                                              acetamide                                          162    18           CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-N,α,α-trimethyl//                                    acetamide                                          163    21           CH.sub.3 NH.sub.2                                                                    N,8-dimethyl-1-propyl//acetamide                   164    25           NH.sub.2                                                                             6-benzyloxy-1-methyl//acetamide                    165    26           (CH.sub.3).sub.2 NH                                                                  1-propyl-N,N,5-trimethyl//                                                    acetamide                                          166    30           n-C.sub.6 H.sub.13 NH.sub.2                                                          1-cyclopropyl-α,α-diethyl-3,3-                                    dimethyl-6-ethoxy-N-hexyl//                                                   acetamide                                          167    35           CH.sub.3 NH.sub.2                                                                    5-iodo-1-isopropyl-N-methyl//                                                 propionamide                                       168    38           NH.sub.2                                                                             1-cyclobutyl-3-methyl-8-nitro-                                                α-propyl//propionamide                       169    41           (CH.sub.3).sub.2 NH                                                                  N,N,α,α,β,3-hexamethyl-1,4,4-                                N                                                                             triethyl//propionamide                             170    44           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,3-dipropyl-5-                                                   methoxy-α-methyl//propionamide               171    46           CH.sub.3 NH.sub.2                                                                    N-methyl-β,1-dipropyl-3,3,5-                                             triethyl//propionamide                             172    48           (CH.sub.3).sub.2 NH                                                                  N,N,1-trimethyl//butyramide                        173    48           CH.sub.3 NH.sub.2                                                                    N,1-dimethyl//butyramide                           174    48           NH.sub.2                                                                             1-methyl//butyramide                               175    48           n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-methyl//butyramide                       176    51           CH.sub.3 NH.sub.2                                                                    1-cyclobutyl-β,γ,γ,4-tetraprop                               yl-                                                                           N,3,3-trimethyl//butyramide                        177    53           (CH.sub.3).sub.2 NH                                                                  N,N,α,α,β,β,γ,.gamm                               a.,4,5-decamethyl-                                                            1-ethyl//butryramide                               178    56           NH.sub.2                                                                             5-bromo-1-cyclopentyl-α,α,β-                                 trimethyl//butyramide                              179    58           CH.sub.3 NH.sub.2                                                                    1,8-diethyl-N,α-dimethyl//                                              butyramide                                         180    60           (C.sub.2 H.sub.5).sub.2 NH                                                           1-propyl-N,N,α,γ-tetraethyl-                                      3,3,5-trimethyl//butyramide                        181    62           n-C.sub.6 H.sub.13 NH.sub.2                                                          α,β-diethyl-3,3-dimethyl-                                          1,5-dipropyl-N-hexyl//butyramide                   __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________           NO. OF THE EXAMPLE   PRODUCT: [(PREFIX LISTED BELOW)-                         IN WHICH STARTING    1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                         MATERIAL IS          INDOLE-1-(SUFFIX LISTED BELOW)]                   EXAMPLE                                                                              PREPARED     AMINE   PREFIX//SUFFIX                                    __________________________________________________________________________    182    2            pyrrolidine                                                                           1-[(1-methyl//propionyl]pyrrolidine               183    2            piperidine                                                                            1-[(1-methyl//propionyl]piperidine                184    2            morpholine                                                                            4-[(1-methyl//propionyl]morpholine                185    2            piperazine                                                                            1-[(1-methyl//propionyl]piperazine                186    2            N-methyl-                                                                             1-methyl-4-[1-methyl//propionyl]-                                     piperazine                                                                            piperazine                                        187    2            N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-methyl//                                     ethanol propionyl]piperazine                              188    4            pyrrolidine                                                                           1-[(1-methyl//carbonyl]pyrrolidine                189    4            morpholine                                                                            4-[(1-methyl//carbonyl]morpholine                 190    5            N-ethyl-                                                                              1-ethyl-4-[(1-ethyl-3-methyl//                                        piperazine                                                                            carbonyl]piperazine                               191    11           piperidine                                                                            1-[(1,4-dimethyl//acetyl]-                                                    piperidine                                        192    12           morpholine                                                                            4-[(1-ethyl//acetyl]morpholine                    193    12           N-piperazine-                                                                         1-(3-hydroxypropyl)-4-                                                propanol                                                                              [(1-ethyl//acetyl]piperazine                      194    13           pyrrolidine                                                                           1-[(1-propyl//acetyl]pyrrolidine                  195    13           morpholine                                                                            4-[(1-propyl//acetyl]morpholine                   196    14           piperidine                                                                            1-[(1-isopropyl//acetyl]piperidine                197    15           piperazine                                                                            1-[(3-methyl-1-propyl//acetyl]-                                               piperazine                                        198    17           N-ethyl-                                                                              1-ethyl-4-[(α,1-dimethyl//acetyl]-                              piperazine                                                                            piperazine                                        199    25           pyrrolidine                                                                           1-[(6-benzyloxyl-1-methyl//acetyl]-                                           pyrrolidine                                       200    26           piperidine                                                                            1-[(5-methyl-1-propyl//acetyl]                                                piperidine                                        201    30           morpholine                                                                            4-[(1-cyclopropyl-α ,α-diethyl-                                   3,3-dimethyl-6-ethoxy//acetyl]-                                               morpholine                                        202    36           piperazine                                                                            1-[8-acetoxy-1-ethyl-α,3,3,4,4-                                         pentamethyl//propionyl//propionyl]piperazine      203    39           N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-cyclo-                                       ethanol propyl-α,α,β,β,4,6-hexam                                ethyl//                                                                       propionyl]piperazine                              204    40           pyrrolidine                                                                           1-[(1,3-dimethyl-α,α-dipropyl//                                   propionyl]pyrrolidine                             205    42           morpholine                                                                            4-[(1-ethyl-β,β,4,4-tetramethyl//                                   propionyl]morpholine                              206    47           N-propyl-                                                                             1-propyl-4-[(1-cyclopropyl-α,β-                            piperazine                                                                            diethyl-6-ethoxy//propionyl]-                                                 piperazine                                        207    48           pyrrolidine                                                                           1-[(1-methyl//butyryl]pyrrolidine                  207a  48           N-piperazine-                                                                         1-(hydroxymethyl)-4-[(1-methyl//                                      methanol                                                                              butyryl]piperazine                                208    50           piperidine                                                                            1-[γ,γ-diethyl-3,3-dimethyl-1-                                    propyl//butyryl]piperidine                        209    52           morpholine                                                                            4-[(7-chloro-α,β,β,γ,.ga                                mma.,4,4-                                                                     heptaethyl-1-methyl//butyryl]-                                                morpholine                                        210    59           piperazine                                                                            1-[(1-butyl-6-fluoro-α,β,γ,3,                                3,4-                                                                          hexamethyl//butyryl]piperazine                    __________________________________________________________________________

                                      TABLE V                                     __________________________________________________________________________                               PRODUCT:                                                  NO. OF THE EXAMPLE  [(PREFIX LISTED BELOW)-1,3,4,9-                           IN WHICH STARTING   TETRAHYDROTHIOPYRANO-[3,4-b]-                             MATERIAL IS         INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED     AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________    211    3            CH.sub.3 NH.sub.2                                                                    N,1-dimethyl//acetamide                            212    3            NH.sub.2                                                                             1-methyl//acetamide                                213    3            n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-methyl//acetamide                        214    3            (CH.sub.3).sub.2 NH                                                                  N,N,1-trimethyl//acetamide,                                                   m.p. 182° C.                                215    3            (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-methyl//acetamide                    216    96           CH.sub.3 NH.sub.2                                                                    N,1-dimethyl//propionamide                         217    96           NH.sub.3                                                                             1-methyl//propionamide                             218    96           (CH.sub.3).sub.2 NH                                                                  N,N,1-trimethyl//propionamide                      219    96           n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-methyl//propionamide                     220    96           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-methyl//propion-                                                amide                                              221    65           CH.sub.3 NH.sub.2                                                                    N,1-dimethyl//carboxamide                          222    65           NH.sub.3                                                                             1-methyl//carboxamide                              223    65           (CH.sub.3).sub.2 NH                                                                  N,N,1-trimethyl//carboxamide                       224    65           n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-methyl//carboxamide                      225    65           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-methyl//carboxamide                  226    66           CH.sub.3 NH.sub.2                                                                    N,3-dimethyl-1-ethyl//carboxamide                  227    69           NH.sub.3                                                                             8-ethyl-propyl//carboxamide                        228    70           (CH.sub.3).sub.2 NH                                                                  1-cyclopropyl-N,N-dimethyl-4-                                                 isopropyl//carboxamide                             229    72           (CH.sub.3).sub.2 NH                                                                  N,N,1,4-tetramethyl//acetamide                     230    73           CH.sub.3 NH.sub.2                                                                    1-ethyl-N-methyl//acetamide                        231    73           NH.sub.3                                                                             1-ethyl//acetamide                                 232    73           (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-ethyl//acetamide                    233    73           n-C.sub.16 H.sub.13 NH.sub.2                                                         1-ethyl-N-hexyl//acetamide                         234    73           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N,1-triethyl//acetamide                          235    74           CH.sub.3 NH.sub.2                                                                    N-methyl-1-propyl//acetamide                       236    74           NH.sub.3                                                                             1-propyl//acetamide                                237    74           (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-propyl//acetamide                   238    74           n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-propyl//acetamide                        239    74           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-propyl//acetamide                    240    75           CH.sub.3 NH.sub.2                                                                    1-isopropyl-N-methyl//acetamide                    241    75           NH.sub.3                                                                             1-isopropyl//acetamide                             242    75           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1-isopropyl//acetamide                 243    76           CH.sub.3 NH.sub.2                                                                    N,3-dimethyl-1-propyl//acetamide                   244    76           NH.sub.3                                                                             3-methyl-1-propyl//acetamide                       245    76           (CH.sub.3).sub.2 NH                                                                  1-propyl-N,N,3-trimethyl//                                                    acetamide                                          246    76           n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-3-methyl-1-propyl//                                                   acetamide                                          247    76           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-3-methyl-1-propyl//                                               acetamide                                          248    78           CH.sub.3 NH.sub.2                                                                    N,α,1-trimethyl//acetamide                   249    78           NH.sub.3                                                                             α,1-dimethyl//acetamide                      250    78           (CH.sub.3).sub.2 NH                                                                  N,N,α,1-tetramethyl//acetamide               251    78           n-C.sub. 6 H.sub.13 NH.sub.2                                                         α,1-dimethyl-N-hexyl//acetamide              252    78           (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-α,1-dimethyl//                                              acetamide                                          253    79           CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-N,α,α-trimethyl//                                    acetamide                                          254    82           CH.sub.3 NH.sub.2                                                                    N,8-dimethyl-1-propyl//acetamide                   255    83           NH.sub.2                                                                             6-bromo-1-propyl//acetamide                        256    89           (CH.sub.3).sub.2 NH                                                                  α,α-diethyl-8-fluoro-N,N,1-                                       trimethyl//acetamide                               257    91           n-C.sub.6 H.sub.13 NH.sub.2                                                          1-cyclopropyl-α,α-diethyl-3,3-                                    dimethyl-6-ethoxy-N-hexyl//                                                   acetamide                                          258    99           NH.sub.2                                                                             1-cyclobutyl-3-methyl-8-nitro-                                                α-propyl//propionamide                       259    102          (CH.sub.3).sub.2 NH                                                                  N,N,α,α,β,3-hexamethyl-1,4,4-                                N                                                                             triethyl//propionamide                             260    105          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,3-dipropyl-5-                                                   methoxy-α-methyl//propionamide               261    107          CH.sub.3 NH.sub.2                                                                    β,1-dipropyl-N-methyl-3,3,5-                                             triethyl//propionamide                             262    108          CH.sub.3 NH.sub.2                                                                    1-cyclopropyl-α,β-diethyl-6-                                       ethoxy-N-methyl//propionamide                      263    109          (CH.sub.3).sub.2 NH                                                                  N,N,1-trimethyl//butyramide                        264    109          CH.sub.3 NH.sub.2                                                                    N,1-dimethyl//butyramide                           265    109          n-C.sub.6 H.sub.13 NH.sub.2                                                          N-hexyl-1-methyl//butyramide                       266    112          CH.sub.3 NH.sub.2                                                                    1-cyclobutyl-β,γ,γ,4-tetraprop                               yl-                                                                           N,3,3-trimethyl//butyramide                        267    113          (CH.sub.3).sub.2 NH                                                                  7-chloro-α,β,β,γ,γ,                               4,4-heptaethyl-                                                               N,N,1-trimethyl//butyramide                        268    117          NH.sub.2                                                                             5-bromo-1-cyclopentyl-α,α,β-                                 trimethyl//butyramide                              269    119          CH.sub. 3 NH.sub.2                                                                   1,8-diethyl-N,α-dimethyl//                                              butyramide                                         270    121          (C.sub.2 H.sub.5).sub.2 NH                                                           1-propyl-N,N,α,γ-tetraethyl-                                      3,3,5-trimethyl//butyramide                        271    123          n-C.sub.6 H.sub.13 NH.sub.2                                                          α,β-diethyl-3,3-dimethyl-1,5-                                      dipropyl-N-hexyl//butyramide                       __________________________________________________________________________

                                      TABLE VI                                    __________________________________________________________________________                                PRODUCT: [(PREFIX LISTED BELOW)-                         NO. OF THE EXAMPLE   1,3,4,9-TETRAHYDROTHIOPYRANO-                            IN WHICH STARTING    [3,4-b]INDOLE-1-(SUFFIX LISTED                           MATERIAL IS          BELOW)]-EXAMPLE PREPARED AMINE PREFIX//SUFFIX     __________________________________________________________________________    272    3            pyrrolidine                                                                           1-[(1-methyl//acetyl]pyrrolidine                  273    3            piperidine                                                                            1-[(1-methyl//acetyl]piperidine                   274    3            morpholine                                                                            4-[(1-methyl//acetyl]morpholine                   275    3            piperazine                                                                            1-[(1-methyl//acetyl]piperazine                   276    3            N-methyl-                                                                             1-methyl-4-[1-methyl//acetyl]-                                        piperazine                                                                            piperazine                                        277    3            N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-methyl//                                     ethanol acetyl]piperazine                                 278    96           pyrrolidine                                                                           1-[(1-methyl//propionyl]-                                                     pyrrolidine                                       279    96           piperidine                                                                            1-[(1-methyl//propionyl]piperidine                280    96           morpholine                                                                            4-[(1-methyl//propionyl]morpholine                281    96           piperazine                                                                            1-[(1-methyl//propionyl]piperazine                282    96           N-methyl-                                                                             1-methyl-4-[1-methyl//propionyl]-                                     piperazine                                                                            piperazine                                        283    96           N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-methyl//                                     ethanol propionyl]piperazine                              284    65           pyrrolidine                                                                           1-[(1-methyl//carbonyl]pyrrolidine                285    65           morpholine                                                                            4-[(1-methyl//carbonyl]morpholine                 286    66           N-ethyl-                                                                              1-ethyl-4-[(1-ethyl-3-methyl//                                        piperazine                                                                            carbonyl]piperzine                                287    72           piperidine                                                                            1-[(1,4-dimethyl//acetyl]-                                                    piperidine                                        288    73           morpholine                                                                            4-[(1-ethyl//acetyl]morpholine                    289    73           N-piperazine-                                                                         1-(3-hydroxypropyl)-4-[(1-ethyl//                                     propanol                                                                              acetyl]piperazine                                 290    74           pyrrolidine                                                                           1-[(1-propyl//acetyl]pyrrolidine                  291    74           morpholine                                                                            4-[(1-propyl//acetyl]morpholine                   292    75           piperidine                                                                            1-[(1-isopropyl//acetyl]piperidine                293    76           piperazine                                                                            1-[(3-methyl-1-propyl//acetyl]-                                               piperazine                                        294    78           N-ethyl-                                                                              1-ethyl-4-[(α,1-dimethyl//acetyl]-                              piperazine                                                                            piperazine                                        295    78           N-methyl-                                                                             1-methyl-4-[(α,1-dimethyl//acetyl]-                             piperazine                                                                            piperazine                                        296    86           pyrrolidine                                                                           1-[(6-benzyloxy-1-methyl//                                                    acetyl]pyrrolidine                                297    87           piperidine                                                                            1-[(5-methyl-1-propyl//acetyl]-                                               piperidine                                        298    91           morpholine                                                                            4-[(1-cyclopropyl-α,α-diethyl-                                    3,3-dimethyl-6-ethoxy//acetyl]-                                               morpholine                                        299    97           piperazine                                                                            1-[(8-acetoxy-1-ethyl-α,3,3,4,4-                                        pentamethyl//propionyl]piperazine                 300    100          N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-cyclo-                                       ethanol propyl-α,α,β,β,4,6-hexam                                ethyl//                                                                       propionyl]piperazine                              301    101          pyrrolidine                                                                           1-[(1,3-dimethyl-α,α-dipropyl//                                   propionyl]pyrrolidine                             302    103          morpholine                                                                            4-[(1-ethyl-β,β,4,4-tetramethyl//                                   propionyl]morpholine                              303    108          N-propyl-                                                                             1-propyl-4-[(1-cyclopropyl-α,β-                            piperazine                                                                            diethyl-6-ethoxy//propionyl]-                                                 piperazine                                        304    109          pyrrolidine                                                                           1-[(1-methyl//butyryl]pyrrolidine                 305    109          N-piperazine-                                                                         1-(hydroxymethyl)-4-[(1-methyl//                                      methanol                                                                              butyryl]piperazine                                306    111          piperidine                                                                            1-[(γ,γ-diethyl-3,3-dimethyl-1-                                   propyl//butyryl]piperidine                        307    113          morpholine                                                                            4-[(7-chloro-α,β,β,γ,.ga                                mma.,4,4-                                                                     heptaethyl-1-methyl//butyryl]-                                                morpholine                                        308    120          piperazine                                                                            1-[(1-butyl-6-fluoro-α,β,γ,3,                                3,4-                                                                          hexamethyl//butyryl] piperazine                   __________________________________________________________________________

EXAMPLE 3091-[2-(Dimethylamino)Ethyl]-1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole[I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ CH₂N(CH₃)₂ ]

A solution ofN,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (5.0g. 0.018 mole), prepared as described in Example 126, is added dropwiseto a cooled, well-stirred mixture of lithium aluminum hydride (1.4 g,0.036 mole) in 200 ml of ether. Stirring is continued for 1 hour at roomtemperature, then the mixture is heated under reflux for 2 hr.

After cooling in an ice-water bath, 6.2 ml of water is added dropwise todestroy the excess hydride. Then 100 ml more of water is added and theether phase decanted. The aqueous phase is extracted once with benzene.The combined organic phases are washed with water, dried over sodiumsulfate, and evaporated to dryness to afford 5 g of oil whichcrystallized on standing. The crystallized product is recrystallizedfrom ether to afford the pure title compound, m.p. 133° - 135° C.,nmr(CDCl₃)δ1.53 (s, 3H), 2.07 (2H), 9.74 (1H), 10.55 (6H).

The corresponding oxalic acid addition salt (oxalate),1-](2-dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indoleoxalate, has m.p. 181° - 183° C. after crystallization frommethanol-ether.

In the same manner but replacing lithium aluminum hydride with anequivalent amount of lithium aluminum hydride-aluminum chloride,aluminum hydride-aluminum chloride, diborane and sodiumborohydride-aluminum chloride, the title compound is also obtained.

In the same manner but replacingN,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide withan equivalent amount of the following amides described in Example 126,

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,n-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-isopropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]pyrrolidine,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]piperidine,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]morpholine,and

1-methyl-4-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-acetyl]piperazine,then there are obtained,

1-(2-aminoethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p.80° - 84° C., ν_(max) ^(CHCl).sbsp.3 3455, 3280cm⁻¹,

1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,m.p. 160° - 163° C., (m.p. of corresponding oxalic acid addition salt,140° - 144° C.),

1-[2-(hexylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-[2-(diethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,m.p. 74°-76° C, m.p. of corresponding maleic acid addition salt,98°-100° C.,

1-[2-(isopropylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-[2-(ethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-methyl-1-[2-(1-pyrrolidinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,

nmr (CDCl₃) δ1.62 (3H), 2.00 (m, 4H), 4.05 (m, 2H),

m.p. of corresponding maleic acid addition salt (maleate), 192° - 193°C.,

1-methyl-1-(2-piperidinoethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole,m.p. 146° - 148° C., m.p. of corresponding maleic acid addition salt,147° - 149° C.,

1-methyl-1-(2-morpholinoethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole,nmr (DMSO-d₆) δ1.50 (3H), 6.07 (2H), 6.87 - 7.65 (m, 4H), 10.86 (1H),m.p. of corresponding maleic acid addition salt, 192° - 193° C., and

1-methyl-1-[2-(4-methyl-1-piperazinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,nmr (CDCl₃) δ1.47 (3H), 2.58 (3H), 3.87 (t, 2H), [m.p. of correspondingmaleic acid addition salt (i.e. dimaleate), 208° - 210° C.],respectively.

By following the procedure of Example 309 but using as starting materialan equivalent amount of one of the amido compounds of formula VII,described in Examples 127 to 308 instead ofN,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, thenthe corresponding compounds of formula I in which R⁷ is hydrogen areobtained. Examples of such compounds of formula I are listed as productsin Tables VII and VIII together with the appropriate starting material,amides of formula VII. In each case the starting material is noted bythe example in which it is prepared.

                                      TABLE VII                                   __________________________________________________________________________           NO. OF THE EXAMPLE                                                     IN WHICH STARTING                                                                    PRODUCT: (PREFIX LISTED BELOW)-                                               MATERIAL IS  1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          EXAMPLE                                                                              PREPARED     INDOLE                                                    __________________________________________________________________________    310    127          1-methyl-1-[3-(methylamino)propyl],                                           nmr (CDC1.sub.3) δ1.48 (3H), 1.87 (4H),                                 2.47 (3H), corresponding oxalic                                               acid addition salt has m.p.                                                   110° C.                                            311    128          1-(3-aminopropyl)-1-methyl                                312    129          1-methyl-1-[ 3-(dimethylamino)-                                               propyl], m.p. 114 - 116° C.,                                           corresponding oxalic acid                                                     addition salt has m.p. 168 - 172° C.               313    130          1-[3-(hexylamino)propyl]-1-methyl                         314    131          1-[3-(diethylamino)propyl]-1-                                                 methyl                                                    315    132          1-methyl-1-[(methylamino)methyl]                                              CHCl.sub.3                                                316    133          1-(aminomethyl)-1-methyl, γ max                                         3465, 3400, 3180, 2930,                                                       corresponding hydrochloric acid                                               addition salt (hydrochloride)                                                 has m.p. 251 - 252° C.                             317    134          1-[(dimethylamino)methyl]-1-                                                  methyl                                                    318    135          1-[(hexylamino)methyl]-1-methyl                           319    136          1-[(ethylamino)methyl]-1-methyl,                                              nmr (DMSO-d.sub.6) δ1.18 (3H),                                          1.62 (3H), 2.80 (2H); correspond-                                             ing hydrochloride acid addition                                               salt has m.p. 245 -  243° C.                       320    137          1-ethyl-3-methyl-1-[(methylamino)-                                            methyl]                                                   321    138          1-cyclopropyl-1-[(dimethylamino)-                                             methyl]-4-isopropyl                                       322    139          1,4-dimethyl-1-[2-(dimethylamino)-                                            ethyl]                                                    323    140          1-ethyl-1-[2-(methylamino)ethyl]                          324    141          1-(2-aminoethyl)-1-ethyl                                  325    142          1-[2-(dimethylamino)ethyl]-1-                                                 ethyl                                                     326    143          1-ethyl-1-[2-(hexylamino)ethyl]                           327    144          1-[2-(diethylamino)ethyll]-1-ethyl                        328    145          1-[2-(methylamino)ethyl]-1-propyl                         329    146          1-(aminoethyl)-1-propyl                                   330    147          1-[2-(dimethylamino)ethyl]-1-                                                 propyl, nmr (CDCl.sub.3) 0.84 (t,3H),                                         1.21 (3, 6H), 2.79 (t,5 = 5.5 cps,                                            2H) corresponding maleic acid                                                 addition salt has m.p. 152 -154° C)                331    148          1-[2-(hexylamino)ethyl]-1-propyl                          332    149          1-[2-(diethylamino)ethyl]-1-propyl                        333    150          1-isopropyl-1-[2-(methylamino)-                                               ethyl]                                                    334    151          1-(2-aminoethyl)-1-isopropyl                              335    152          1-[2-(diethylamino)ethyl]-1-                                                  isopropyl                                                 336    153          3-methyl-1-[2-(methylamino)ethyl]-                                            1-propyl                                                  337    154          1-[2-(dimethylamino)ethyl]-3-                                                 methyl-1-propyl                                           338    155          1-[2-(hexylamino)ethyl]-3-methyl]-                                            1-propyl                                                  339    156          1-[2-(diethylamino)ethyl]-3-                                                  methyl-1-propyl                                           340    157          1-[1-methyl-2-(methylamino)ethyl]-                                            1-methyl                                                  341    158          1-(2-amino-1-methyl-ethyl)-1-                                                 methyl                                                    342    159          1-[2-(dimethylamino)-1-methyl-                                                ethyl]-1-methyl                                           343    160          1-[2-(hexylamino)-1-methyl-ethyl]-                                            1-methyl                                                  344    161          1-[2-(diethylamino)-1-methyl-ethyl]-                                          1-methyl                                                  345    162          1-cyclohexyl-1-[1,1-dimethyl-2-                                               (methylamino)ethyl]                                       346    163          8-methyl-1-[2-(methylamino)ethyl]-                                            1-propyl                                                  347    164          1-(2-aminoethyl)-6-benzyloxy-1-                                               methyl                                                    348    165          1-[2-(dimethylamino)ethyl]-5-                                                 methyl-1-propyl                                           349    166          1-cyclopropyl-1-[1,1-diethyl-2-                                               (hexylamino)ethyl]3,3-dimethyl-                                               6-ethoxy                                                  350    167          5-iodo-1-isopropyl-1-[3-(methyl-                                              amino)propyl]                                             351    168          1-(3-amino-2-propyl-propyl)-1-                                                cyclobutyl-3-methyl-8-nitro                               352    169          1-[3-(dimethylamino)-1,2,2-                                                   trimethyl-propyl]-1,4,4-triethyl                          353    170          1-[3-(diethylamino)-2-methyl-                                                 propyl]-1,3-dipropyl-5-methoxy                            354    171          1-[1-propyl-3-(methylamino)-                                                  propyl]-1-propyl-3,3,5-trimethyl                          355    172          1-[4-(dimethylamino)butyl]-1-                                                 methyl                                                    356    173          1-[4-(methylamino)butyl]-1-methyl                         357    174          1-(4-aminobutyl)-1-methyl                                 358    175          1-[4-(hexylamino)butyl]-1-methyl                          359    176          1-cyclobutyl-3,3-dimethyl-1-                                                  [4-(methylamino)-1,1,2-tripropyl-                                             butyl]-4-propyl                                           360    177          4,5-dimethyl-1-ethyl-1-[4-                                                    dimethylamino)-1,1,2,2,3,3-                                                   hexamethylbutyl]                                          361    178          1-(4-amino-2,3,3-trimethyl-butyl)-                                            5-bromo-1-cyclopentyl                                     362    179          1,8-diethyl-1-[3-methyl-4-                                                    (methylamino)butyl]                                       363    180          1-[1,3-diethyl-4-(diethylamino)-                                              butyl]-1-propyl-3,3,5-trimethyl                           364    181          1-[2,3-diethyl-4-(hexylamino)-                                                butyl]-3,3-dimethyl-1,5-dipropyl                          365    182          1-methyl-1-[3-(1-pyrrolidinyl)-                                               propyl], m.p. 124 - 127° C.                        366    183          1-methyl-1-(3-piperidinopropyl)                           367    184          1-methyl-1-(3-morpholinopropyl)                           368    185          1-methyl-1-(3-piperazinopropyl)                           369    186          1-methyl-1-[3-(4-methyl-1-                                                    piperazinyl)propyl]                                       370    187          1-{3-[4-(2-hydroxyethyl)-1-                                                   piperazinyl]propyl}1-methyl                               371    188          1-methyl-1-[(1-pyrrolidinyl)-                                                 methyl]                                                   372    189          1-methyl-1-(morpholinomethyl)                             373    190          1-ethyl-3-methyl-1-[(4-methyl-1-                                              piperazinyl)methyl]                                       374    191          1,4-dimethyl-1-(2-piperidinoethyl)                        375    192          1-ethyl-1-(2-morpholinoethyl)                             376    193          1-ethyl-1-{2-[4-(3-hydroxypropyl)-                                            1-piperazinyl]ethyl}                                      377    194          1-propyl-1-[2-(1-pyrrolidinyl)-                                               ethyl]                                                    378    195          1-propyl-1-(2-morpholinoethyl)                            379    196          1-isopropyl-1-(2-piperidinoethyl)                         380    197          3-methyl-1-(2-piperazinoethyl)-                                               1-propyl                                                  381    198          1-ethyl-1-[1-methyl-2-(4-methyl-                                              1-piperazinyl)ethyl]                                      382    199          6-benzyloxy-1-methyl-1-[2-(1-                                                 pyrrolidinyl)ethyl]                                       383    200          5-methyl-1-(2-piperidinoethyl)-                                               1-propyl                                                  384    201          1-cyclopropyl-1-(1,1-diethyl-2-                                               morpholinoethyl)-3,3-dimethyl-6-                                              ethoxy                                                    385    202          8-acetoxy-1-ethyl-3,3,4,4-                                                    tetramethyl-1-(2-methyl-3-                                                    piperazinopropyl)                                         386    203          1-cyclopropyl-4,6-dimethyl-1-                                                 {3-[4-(2-hydroxyethyl)-1-piperazio-                                           yl]-1,1,2,2-tetramethylpropyl}                            387    204          1,3-dimethyl-1-[2,2-dipropyl-3-                                               (1-pyrrolidinyl)propyl]                                   388    205          4,4-dimethyl-1-ethyl-1-(1,1-                                                  dimethyl-3-morpholinopropyl)                              389    206          1-cyclopropyl-1-[1,2-diethyl-3-                                               (4-propyl-1-piperazinyl)propyl]-                                              6-ethoxy                                                  390    207          1-methyl-1-[4-(1-pyrrolidinyl)-                                               butyl]                                                    391     207a        1-{4-[4-(hydroxymethyl)-1-                                                    piperazinyl]butyl}-1-methyl                               392    208          1-[(1,1-diethyl-4-piperidino)buty                                             3,3-dimethyl-1-propyl                                     393    209          7-chloro-4,4-diethyl-1-methyl-1-                                              (4-morpholino-1,1,2,2,3-                                                      pentaethylbutyl)                                          394    210          1-butyl-6-fluoro-1-(4-piperazino-                                             1,2,3-trimethylbutyl)-3,3,4-                                                  trimethyl                                                 __________________________________________________________________________

                                      TABLE VIII                                  __________________________________________________________________________           NO. OF THE EXAMPLE                                                            IN WHICH STARTING                                                                           PRODUCT: (PREFIX LISTED BELOW)-                                 MATERIAL IS   1,3,4,9-TETRAHYDROTHIOPYRANO-                            EXAMPLE                                                                              PREPARED      [3,4-b]INDOLE                                            __________________________________________________________________________    395    211           1-methyl-1-[2-(methylamino)ethyl]                        396    212           1-(2-aminoethyl)-1-methyl                                397    213           1-[(2-hexylamino)ethyl]-1-methyl                         398    214           1-[2-(dimethylamino)ethyl]-1-                                                 methyl, m.p. 119 - 121° C.                        399    215           1-[2-(diethylamino)ethyl]-1-                                                  methyl                                                   400    216           1-methyl-1-[3-(methylamino)propyl]                       401    217           1-(3-aminopropyl)-1-methyl                               402    218           1-[3-(dimethylamino)propyl]-1-                                                methyl                                                   403    219           1-[3-(hexylamino)propyl]-1-methyl                        404    220           1-[3-(diethylamino)propyl]-1-                                                 methyl                                                   405    221           1-methyl-1-[(methylamino)methyl]                         406    222           1-(aminomethyl)-1-methyl                                 407    223           1-[(dimethylamino)methyl]-1-                                                  methyl                                                   408    224           1-[(hexylamino)methyl]-1-methyl                          409    225           1-[(diethylamino)methyl]-1-                                                   methyl                                                   410    226           1-ethyl-3-methyl-1-[(methylamino)-                                            methyl]                                                  411    228           1-cyclopropyl-1-[(dimethylamino)-                                             methyl]-4-isopropyl                                      412    229           1,4-dimethyl-1-[2-(dimethylamino)-                                            ethyl]                                                   413    230           1-ethyl-1-[2-(methylamino)ethyl]                         414    231           1-(2-aminoethyl)-1-ethyl                                 415    232           1-[2-(dimethylamino)ethyl]-1-                                                 ethyl                                                    416    233           1-ethyl-1-[2-(hexylamino)ethyl]                          417    234           1-[2-(diethylamino)ethyl]-1-ethyl                        418    235           1-[2-(methylamino)ethyl]-1-propyl                        419    236           1-(aminoethyl)-1-propyl                                  420    237           1-[2-(dimethylamino)ethyl]-1-propyl                      421    238           1-[2-(hexylamino)ethyl]-1-propyl                         422    239           1-[2-(diethylamino)ethyl]-1-propyl                       423    240           1-isopropyl-1-[2-(methylamino)-                                               ethyl]                                                   424    241           1-(2-aminoethyl)-1-isopropyl                             425    242           1-[2-(diethylamino)ethyl]-1-                                                  isopropyl                                                426    243           3-methyl-1-[2-(methylamino)ethyl]-                                            1-propyl                                                 427    245           1-[2-(dimethylamino)ethyl]-3-                                                 methyl-1-propyl                                          428    246           1-[2-(hexylamino)ethyl]-3-methyl-                                             1-propyl                                                 429    247           1-[2-(diethylamino)ethyl]-3-methyl                                            1-propyl                                                 430    248           1-[1-methyl-2-(methylamino)ethyl]-                                            1-methyl                                                 431    249           1-(2-amino-1-methylethyl)-1-                                                  methyl                                                   432    250           1-[2-(dimethylamino)-1-methyl-                                                ethyl]-1-methyl                                          433    251           1-[2-(hexylamino)-1-methyl-ethyl]-                                            1-methyl                                                 434    252           1-[2-(diethylamino)-1-methyl-                                                 ethyl]-1-methyl                                          435    253           1-cyclohexyl-1-[1,1-dimethyl-2-                                               (methylamino)ethyl]                                      436    254           8-methyl-1-[2-(methylamino)ethyl]-                                            1-propyl                                                 437    255           1-(2-aminoethyl)-6-bromo-1-propyl                        438    257           1-cyclopropyl-1-[1,1-diethyl-2-                                               (hexylamino)ethyl]-3,3-dimethyl-                                              6-ethoxy                                                 439    258           1-(3-amino-2-propyl-propyl)-1-                                                cyclobutyl-3-methyl-8-nitro                              440    259           1-[3-(dimethylamino)-1,2,2-                                                   trimethyl-propyl]-1,4,4-triethyl                         441    260           1-[3-(diethylamino)-2-methyl-                                                 propyl]-1,3-dipropyl-5-methoxy                           442    261           1-[1-propyl-3-(methylamino)-                                                  propyl]-4-propyl-3,3,5-trimethyl                         443    263           1-[4-(dimethylamino)butyl]-1-                                                 methyl                                                   444    264           1-[4-(methylamino)butyl]-1-                                                   methyl                                                   445    265           1-[4-(hexylamino)butyl]-1-methyl                         446    266           1-cyclobutyl-3,3-dimethyl-1-                                                  [4-(methylamino)-1,1,2-tripropyl-                                             butyl]-4-propyl                                          447    267           7-chloro-4,4-diethyl-1-[4-                                                    dimethylamino-1,1,2,2,3-                                                      pentaethylbutyl]-1-methyl                                448    268           1-(4-amino-2,3,3-trimethyl-                                                   butyl)-5-bromo-1-cyclopentyl                             449    269           1,8-diethyl-1-[3-methyl-4-                                                    (methylamino)butyl]                                      450    270           1-[1,3-diethyl-4-(diethylamino)-                                              butyl]-1-propyl-3,3,5-trimethyl                          451    271           1-[2,3-diethyl-4-(hexylamino)-                                                butyl]-3,3-dimethyl-1,5-dipropyl                         452    272           1-methyl-1-[2-(1-pyrrolidinyl)-                                               ethyl]                                                   453    273           1-methyl-1-(2-piperidinoethyl)                           454    274           1-methyl-1-(2-morpholinoethyl)                           455    275           1-methyl-1-(2-piperazinoethyl)                           456    276           1-methyl-1-[2-(4-methyl-1-                                                    piperazinyl)ethyl]                                       457    277           1-{2-[4-(2-hydroxyethyl)-1-                                                   piperazinyl]ethyl}-1-methyl                              458    278           1-methyl-1-[3-(1-pyrrolidinyl)-                                               propyl]                                                  459    279           1-methyl-1-(3-piperidinopropyl)                          460    280           1-methyl-1-(3-morpholinopropyl)                          461    281           1-methyl-1-(3-piperazinopropyl)                          462    282           1-methyl-1-[3-(4-methyl-1-                                                    piperazinyl)propyl]                                      463    283           1-{3-[4-(2-hydroxyethyl)-1-                                                   piperazinyl]propyl}-1-methyl                             464    284           1-methyl-1-[(1-pyrrolidinyl)-                                                 methyl]                                                  465    285           1-methyl-1-(morpholinomethyl)                            466    286           1-ethyl-3-methyl-1-[(4-ethyl-1-                                               piperazinyl)methyl]                                      467    287           1,4-dimethyl-1-(2-piperidino-                                                 ethyl)                                                   468    288           1-ethyl-1-(2-morpholinoethyl)                            469    289           1-ethyl-1-{2-[4-(3-hydroxy-                                                   propyl)-1-piperazinyl]ethyl}                             470    290           1-propyl-1-[2-(1-pyrrolidinyl)                                                ethyl]                                                   471    291           1-(2-morpholinoethyl)-1-propyl                           472    292           1-isopropyl-1-(2-piperidinoethyl)                        473    293           3-methyl-1-(2-piperazinoethyl)-                                               1-propyl                                                 474    295           1-methyl-1-[1-methyl-2-(4-                                                    methyl-1-piperazinyl)ethyl]                              475    296           6-benzyloxy-1-methyl-1-[2-(1-                                                 pyrrolidinyl)ethyl]                                      476    297           5-methyl-1-(2-piperidinoethyl)-                                               1-propyl                                                 477    298           1-cyclopropyl-1-(1,1-diethyl-                                                 2-morpholinoethyl-3,3-dimethyl-                                               6-ethoxy                                                 478    299           8-acetoxy-1-ethyl-3,3,4,4-                                                    tetramethyl-1-(2-methyl-3-                                                    piperazinopropyl)                                        479    300           1-cyclopropyl-4,6-dimethyl-1-                                                 {3-[4-(2-hydroxyethyl)-1-                                                     piperazinyl]-1,1,2,2-                                                         tetramethylpropyl}                                       480    301           1,3-dimethyl-1-[2,2-dipropyl-                                                 3-(1-pyrrolidinyl)propyl]                                481    302           4,4-dimethyl-1-ethyl-1-(1,1-                                                  dimethyl-3-morpholinopropyl)                             482    303           1-cyclopropyl-6-ethoxy-1-                                                     [1,2-diethyl-3-(4-propyl-1-                                                   piperazinyl)propyl]                                      483    304           1-methyl-1-[4-(1-pyrrolidinyl)-                                               butyl]                                                   484    305           1-{4-[4-(hydroxymethyl)-                                                      piperazinyl]butyl}-1-methyl                              485    306           1-[(1,1-diethyl-4-piperidino)-                                                butyl]-3,3-dimethyl-1-propyl                             486    307           7-chloro-4,4-diethyl-1-methyl-                                                1-(4-morpholino-1,1,2,2,3-                                                    pentaethylbutyl)                                         487    308           1-butyl-6-fluoro-1-(4-                                                        piperazino-1,2,3-trimethylbutyl)-                                             3,3,4-trimethyl                                          __________________________________________________________________________

EXAMPLE 488 1,9-Dimethyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-1-AceticAcid (VII; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X = O and Z = CH₂COOH

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (10 g.,0.04 mole), prepared as described in Example 1, in 150 ml. oftetrahydrofuran is added dropwise to a stirred suspension of sodiumhydride (4.4 g. of 55% dispersion) in 200 ml. of tetrahydrofuran. Thismixture is heated at 50° C. with stirring for 2 hr. Methyl iodide (14.2g. 0.1 mole) is added dropwise and heating and stirring is continued fora further 2 hr.

After cooling, water is added until the solution is clear. Thetetrahydrofuran is evaporated off under reduced pressure, the residue ispartitioned between water and benzene. The aqueous phase is washed oncewith benzene, made acidic with HCl, and extracted with benzene (3x). Theorganic phase is washed with water, dried over sodium sulfate andtreated wih charcoal. The organic layer is evaporated. The residue iscrystallized from benzene and then ether-petroleum ether to afford thetitle compound, m.p. 105° - 108° C., nmr (CDCl₃) δ1.73 (S, 3H), 2.83 (t,J = 5.5, 2H), 3.0 (2H), 3.68 (3H), 4.08 (t, J = 5.5, 2H), 7.34 (4H),9.47 (1H).

In the same manner but replacing methyl iodide with an equivalent amountof ethyl iodide, or propyl iodide, the N-ethyl analog of the titlecompound,9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid,m.p. 134° - 136° C., and the N-propyl analog of the title compound,1-methyl-9-propyl- 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid,m.p. 120° - 122° C., are obtained, respectively.

By following the procedure of Example 488 but using as starting materialan equivalent amount of the acid compounds of formula VII, in which R⁷is hydrogen, described in Examples 1 to 125, inclusive, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and usingan equivalent amount of an appropriate organic halide, then thecorresponding N-alkylated acid compounds of formula I are obtained.Examples of these latter compounds are listed as products in Tables IXand X together with the appropriate starting material of formula VII andorganic halide used for their preparation. In each case the startingmaterial is noted by the Example in which it is prepared.

                                      TABLE IX                                    __________________________________________________________________________           NO. OF THE EXAMPLE        PRODUCT: [(PREFIX LISTED BELOW)-                    IN WHICH STARTING         1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                    MATERIAL IS  ORGANIC      INDOLE-(SUFFIX LISTED BELOW)]                EXAMPLE                                                                              PREPARED     HALIDE       PREFIX//SUFFIX                               __________________________________________________________________________    489     1           CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-methyl//acetic acid,                                                m.p. 103-105° C.                      490     1           CH.sub.2CHBr 1-methyl-9-vinyl//acetic acid                491     1           CHCCH.sub.2 Br                                                                             1-methyl-9-propargyl//acetic acid            492     2           n-C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic acid            493     2           CH.sub.3 I   1,9-dimethyl//propionic acid                 494     2                                                                                          ##STR56##   1-methyl-9-phenethyl//propionic acid         495     2           1-(3-chloropropyl)-                                                                        1-methyl-9-(3-piperidinopropyl)//                                piperazine   propionic acid                               496     4           1-(2-chloroethyl)-                                                                         1-methyl-9-[2-(1-pyrrolidinyl)-                                  pyrrolidine  ethyl]//carboxylic acid                      497     6           CHCCH.sub.2 Br                                                                             1,3-diisopropyl-6-methyl-9-                                                   propargyl//carboxylic acid                   498     7           CH.sub.3 I   6-hydroxy-1,3,3,9-tetramethyl//                                               carboxylic acid                              499     8           CH.sub.3 CHCHBr                                                                            8-ethyl-9-(1-propenyl)-1-propyl//                                             carboxylic acid                              500    10           C.sub.2 H.sub.5 Br                                                                         1-cyclopentyl-4,4,9-triethyl-3,3-                                             dimethyl//carboxylic acid                    501    12           CH.sub.3 I   1-ethyl-9-methyl//acetic acid                502    12           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                     503    12           CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-ethyl//acetic acid                 504    12           2-(dimethylamino)-                                                                         9-[2-(dimethylamino)ethyl]//acetic                               ethyl chloride                                                                             acid                                         505    13           CH.sub.3 I   9-methyl-1-propyl//acetic acid               506    13           n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                    507    13           CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-propyl//acetic acid                508    13           CH.sub.2C(CH.sub.3)CH.sub.2 Br                                                             9-methallyl-1-propyl//acetic acid            509    14                                                                                          ##STR57##   9-benzyl-1-isopropyl//acetic acid            510    14           CH.sub.2CHBr 1-isopropyl-9-vinyl//acetic acid             511    15           n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl-3-methyl//acetic acid           512    16           CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1,4-diethyl-3-methyl//                                                acetic acid                                  513    17           CH.sub.3 I   α,1,9-trimethyl//acetic acid           514    18           n-C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                      N                                                                             propyl//acetic acid                          515    19           CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-t-butyl//acetic acid               516    20           CH.sub.2CHCH.sub.2 I                                                                       9-allyl-1-butyl//acetic acid                 517    23           CH.sub.3 Cl  1,9-dimethyl-6-methoxy//acetic                                                acid, m.p. 129-132° C.                518    28           CH.sub.2CHBr 6-nitro-1-propyl-9-vinyl//acetic                                              acid                                         519    32           CHCHCH.sub.2 Br                                                                            α,3-dimethyl-1-ethyl-9-propargyl-                                       4,4,5-tripropyl//acetic acid                 520    34           CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-t-butyl-α,α-diisopr                                     opyl-                                                                         3,3,4,4,5-pentaethyl//acetic acid            521    37           C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-(propyl)-β,β,9-                                         triethyl//propionic acid                     522    38           CH.sub.3 I   1-cyclobutyl-3,9-dimethyl-8-                                                  nitro-α-propyl//propionic acid         523    41           CH.sub.2C(CH.sub.3)CH.sub.2 Cl                                                             1,4,4-triethyl-9-methallyl-α,.alpha                                     .,β-                                                                     3-tetramethyl//propionic acid                524    45                                                                                          ##STR58##   1-methyl ,α,β,β,3-penta-                                      thyl-9-phenethyl//propionic acid             525    47           1-(3-chloro- 1-cyclopropyl-α,β-diethyl-6-                          propyl)piperazine                                                                          ethoxy-9-(3-piperidinopropyl)//                                               propionic acid                               526    48           CH.sub.3 I   1,9-dimethyl//butyric acid                   527    48                                                                                          ##STR59##   9-benzyl-1-methyl//butyric acid              528    49           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//butyric                                       acid                                         529    51           CH.sub.2CHBr 1-cyclobutyl-3,3-dimethyl-β,γ,                                     γ,-                                                                     4-tetrapropyl-9-vinyl//butyric                                                acid                                         530    52           CH.sub.2CHBr 7-chloro-α,β,β,γ,.g                                     amma.,4-heptaethyl-1-                                                         methyl-9-vinyl//butyric acid                 531    58           C.sub.2 H.sub.5 I                                                                          α-methyl-1,8,9-triethyl//butyric                                        acid                                         532    62           CH.sub.3 I   α,β-diethyl-1,5-dipropyl-3,3,9                                     -                                                                             trimethyl//butyric acid                       532a   64a         CH.sub.3 l   1,5,9-trimethyl//acetic acid,                                                 m.p. 132-134°  C.                      532b  25           C.sub.2 H.sub.5 Br                                                                         6-benxyloxy-9-ethyl-1-methyl//                                                acetic acid, nmr (CDCl.sub.3) δ                                         1.73                                                                          (s,3H), 5.12 (s,2H).                          532c  64b          CH.sub.3 l   5-chloro-1,9-dimethyl//acetic                                                 acid m.p. 105-110° C                   532d  784          CH.sub.3 l   6-benzyloxy-1,9-diemthyl//acetic                                              acid, m.p. 167-168° C.                __________________________________________________________________________

                                      table x                                     __________________________________________________________________________           no. of the example       product: [(prefix listed below)-                     in which starting        1,3,4,9-tetrahydrothiopyrano[3,4-b]-                 MATERIAL IS  ORGANIC     INDOLE-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                              PREPARED     HALIDE      PREFIX//SUFFIX                                __________________________________________________________________________    533     3           CH.sub.2CHCH.sub.2 Br                                                                     9-allyl-1-methyl//acetic acid                 534     3           CH.sub.3 I  1,9-dimethyl//acetic acid                     535     3           4-(2-chloroethyl)-                                                                        1-methyl-9-(2-morpholinoethyl)//                                  morpholine  acetic acid                                   536    96           n-C.sub.3 H.sub.7 I                                                                       1-methyl-9-propyl//propionic acid             537    96           CH.sub.3 I  1,9-dimethyl//propionic acid                  538    96           CHCCH.sub.2 Br                                                                            1-methyl-9-propargyl//propionic                                               acid                                          539    96           CH.sub.2CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//propionic acid              540    65           CH.sub.3 I  1,9-dimethyl//carboxylic acid                 541    65           1-(3-chloropropyl)-                                                                       1-methyl-9-(3-piperidinopropyl)//                                 piperidine  carboxylic acid                               542    68           CH.sub.3 I  6-hydroxy-1-(1-propyl)-3,3,9-                                                 trimethyl//carboxylic acid                    543    70           CH.sub.3 CHCHBr                                                                           1-cyclopropyl-4-isopropyl-9-                                                  (1-propenyl)//carboxylic acid                 544    73           CH.sub.3 I  1-ethyl-9-methyl//acetic acid                 545    73           C.sub.2 H.sub.5 Cl                                                                        1,9-diethyl//acetic acid                      546    73           4-(2-chloroethyl)-                                                                        1-ethyl-9-(2-morpholinoethyl)//                                   morpholine  acetic acid                                   547    73           CHCCH.sub.2 Br                                                                            1-ethyl-9-propargyl//acetic acid              548    74           CH.sub.3 I  9-methyl-1-propyl//acetic acid                549    74           n-C.sub.3 H.sub.7 Cl                                                                      1,9-dipropyl//acetic acid                     550    74           CH.sub.2CHCH.sub.2 Br                                                                     9-allyl-1-propyl//acetic acid                 551    74           CH.sub.2C(CH.sub.3)CH.sub.2 Br                                                            9-methallyl-1-propyl//acetic acid             552    75           CH.sub.3 I  9-methyl-1-isopropyl//acetic acid             533    75           CH.sub.2CHBr                                                                              1-isopropyl-9-vinyl//acetic acid              554    76           n-C.sub.3 H.sub.7 Cl                                                                      1,9-dipropyl-3-methyl//acetic acid            555    76                                                                                          ##STR60##  9-benzyl-3-methyl-1-propyl//acetic acid       556    78           CH.sub.3 I  α,1,9-trimethyl//acetic acid            557    79           n-C.sub.3 H.sub.7 Cl                                                                      1-cyclohexyl-α,α-dimethyl-9-                                      propyl//acetic acid                           558    84           CH.sub.3 Cl 1,9-dimethyl-6-methoxy//acetic acid           559    89           CH.sub.2CHBr                                                                              α,α-diethyl-1-methyl-9-vinyl-8                                    -                                                                             fluoro//acetic acid                           560    93           C.sub.2 H.sub.5 Cl                                                                        α,3-dimethyl-1,9-diethyl-1-phenyl-                                      4,4,5-tripropyl//acetic acid                  561    95           CH.sub.2CHCH.sub.2 Br                                                                     9-allyl-1-t-butyl-α,α-diisopro                                    pyl-                                                                          3,3,4,4,5-pentaethyl//acetic acid             562    98           C.sub.2 H.sub.5 I                                                                         7-hydroxy-1-propyl-β,β,9-                                           triethyl//propionic acid                      563    99           CH.sub.3 I  1-cyclobutyl-3,9-dimethyl-8-nitro-                                            α-propyl//propionic acid                564    106          CH.sub.2CHCl                                                                              1-methyl-6-nitro-α,α,β,.b                                    eta.,3-penta-                                                                 ethyl-9-vinyl//propionic acid                 565    108          C.sub.2 H.sub.5 Cl                                                                        1-cyclopropyl-6-ethoxy-α,β,9-                                      triethyl//propionic acid                      566    109          CH.sub.3 1  1,9-dimethyl//butyric acid                    567    109          CH.sub.2CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//butyric acid                568    110          C.sub.2 H.sub.5 Cl                                                                        1,9-diethyl-γ,3-dimethyl//butyric                                       acid                                          569    112          CH.sub.2CHBr                                                                              1-cyclobutyl-3,3-dimethyl-β,γ,.                                    gamma.,4-                                                                     tetrapropyl-9-vinyl//butyric acid             570    119          C.sub.2 H.sub.5 I                                                                         α-methyl-1,8,9-triethyl//butyric                                        acid                                          __________________________________________________________________________

EXAMPLE 571

By following the procedure of Example 488 but using as the startingmaterial on equivalent amount of the ester compounds of formula I inwhich R⁷ is hydrogen, obtained prior to hydrolysis in Examples 1 and 3to 125, inclusive, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and usingan equivalent amount of the appropriate organic halide, then thecorresponding N-alkylated ester compound of formula I in which R⁷ islower alkyl, lower alkenyl, propargyl or phenyl(lower)-alkyl isobtained.

For example, when following the procedure of Example 488, thereplacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-aceticacid by an equivalent amount of its corresponding ethyl ester, describedin Example 1, and then use of the same alkyl halide, methyl iodide,affords 1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-aceticacid ethyl ester.

Similarly, the replacement of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by anequivalent amount of1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methylester, described in Example 3, affords1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acidmethyl ester.

By following the procedure of Example 126 but using as starting materialan equivalent amount of one of the N-alkylated acid compounds of formulaI, described in Examples 488 to 570, inclusive, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and usingan equivalent amount of an appropriate amine such as ammonia or aprimary or secondary amine, described in Example 126, then thecorresponding amide compound of formula I in which R⁷ is lower alkyl,lower alkenyl, propargyl phenyl(lower)alkyl and amino(lower)alkyl isobtained. Examples of such amides are listed as products in Tables XI,XII, XIII, and XIV together with the appropriate starting material,noted by the example in which it is prepared, and the amine used for thepreparation of the amide.

                                      TABLE XI                                    __________________________________________________________________________           NO. OF THE EXAMPLE  PRODUCT: [(PREFIX LISTED BELOW)-                          IN WHICH STARTING   1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS         INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED     AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________    572    488 (title compound)                                                                       (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//acetamide                     573    488 (title compound)                                                                       CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//acetamide, m.p.                                              136 - 138° C.                               574    488 (title compound)                                                                       NH.sub.3                                                                             1,9-dimethyl//acetamide, m.p.                                                 105 - 106° C.                               575    488 (title compound)                                                                       n-C.sub.6 H.sub.13 NH.sub.2                                                          1,9-dimethyl-N-hexyl//acetamide                    576    488 (title compound)                                                                       (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,9-dimethyl//acetamide                577    488 (N-ethyl analog)                                                                       (CH.sub.3).sub.2 NH                                                                  9-ethyl-N,N,1-trimethyl//acetamide                 578    488 (N-ethyl analog)                                                                       CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-ethyl//acetamide,                                              m.p. 108 - 109° C.                          579    488 (N-ethyl analog)                                                                       NH.sub.3                                                                             9-ethyl-1-methyl//acetamide, m.p.                                             130 - 133° C.                               580    488 (N-propyl analog)                                                                      (CH.sub.3).sub.2 NH                                                                  9-propyl-N,N,1-trimethyl//acetamide,                                          m.p. 84 - 87° C.                            581    488 (N-propyl analog)                                                                      CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-propyl//acetamide                   582    489          CH.sub.3 NH.sub.2                                                                    9-allyl-N,1-dimethylacetamide                      583    491          (CH.sub.3).sub. 2 NH                                                                 9-propargyl-N,N,1-trimethyl//                                                 acetamide                                          584    493          (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//propionamide                  585    493          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//propionamide, m.p.                                           148 - 150° C.                               586    493          (C.sub.2 H.sub.5).sub.2 NH                                                           1,9-dimethyl-N,N-diethyl//                                                    propionamide                                       587    495          NH.sub.3                                                                             1-methyl-9-(3-piperidinopropyl)//                                             propionamide                                       588    495          (CH.sub.3).sub.2 NH                                                                  9-(3-piperidinopropyl-N,N,1-                                                  trimethyl//propionamide                            589    497          CH.sub.3 NH.sub.2                                                                    1,3-diisopropyl-N,6-dimethyl-9-                                               propargyl//carboxamide                             590    498          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-6-hydroxy-1,3,3,9-                                                tetramethyl//carboxamide                           591    501          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-ethyl//acetamide                    592    503          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N,1-triethyl//acetamide                  593    504          (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-9-[2-(dimethylamino)-                                            ethyl]-1-ethyl//acetamide                          594    505          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-propyl//acetamide                   595    507          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N-diethyl-1-propyl//                                                acetamide                                          596    514          CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-9-propyl-N,α,α-                                      trimethyl//acetamide                               597    516          n-C.sub.6 H.sub.13 NH.sub.2                                                          9-allyl-1-butyl-N-hexyl//acetamide                 598    517          (CH.sub.3).sub.2 NH                                                                  6-methoxy-N,N,1,9-tetramethyl//                                               acetamide, m.p. 118 - 120° C.               599    519          CH.sub.3 NH.sub.2                                                                    1-ethyl-9-propargyl-4,4,5-tripropyl-                                          N,α,3-trimethyl//acetamide                   600    524          (C.sub. 2 H.sub.5).sub.2 NH                                                          N,N,α,α,β,β,3-heptaethyl-                               1-                                                                            methyl-6-nitro-9-phenethyl//                                                  propionamide                                       601    525          (C.sub.2 H.sub.5).sub.2 NH                                                           1-cyclopropyl-6-methoxy-N,N,α,β,9-                                 pentaethyl-9-vinyl//propionamide                   602    526          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//butyramide                        603    527          (CH.sub.3).sub.2 NH                                                                  9-benzyl-N,N,1-trimetyl//                                                     butyramide                                         604    528          NH.sub.2                                                                             1,9-diethyl-γ,3-dimethyl//                                              butyramide                                         605    532          CH.sub.3 NH.sub.2                                                                    α,β-diethyl-1,5-dipropyl-N,3,3,9-                                  tetramethyl//butyramide                            605a   532a         (CH.sub.3).sub.2 NH                                                                  N,N,1,5,9-pentamethyl//acetamide,                                             nmr (CDCl.sub.3) ∂ 1.75 (s,3H),                                  2.66                                                                          (s,3H), 2.96 (s,3H), 3.08 (s,3H),                                             3.78 (s,3H)                                        605b   532b         (CH.sub.3).sub.2 NH                                                                  6-benzyloxy-9-ethyl-N,N,1-trimethyl//                                         acetamide, ν.sub.max.sup.CHCl.sub.3 . 1650                                 cm.sup.-1                                          605c   532c         (CH.sub.3).sub.2 NH                                                                  5-chloro-N,N,1,9-tetramethyl//                                                acetamide, nmr (CDCl.sub.3) ∂                                    1.72                                                                          (s,3H), 2.93 (s,3H), 3.80 (s,3H),                                             3.77 (s,3H)                                        605d   532d         (CH.sub.3).sub.2 NH                                                                  6-benzyloxy-N,N,1,9-tetramethyl//                                             acetamide nmr (CDCl.sub.3) ∂                                     1.73                                                                          (s,3H), 2.95 (s,3H), 3.05 (s,3H),                                             3.75 (s,3H), 5.12 (s,2H)                           __________________________________________________________________________

                                      TABLE XII                                   __________________________________________________________________________           NO. OF THE EXAMPLE  PRODUCT: (PREFIX LISTED BELOW)-                           IN WHICH STARTING   (1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                         MATERIAL IS         INDOLE-1-YL)-(SUFFIX LISTED BELOW)]                EXAMPLE                                                                              PREPARED     AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________    606    488 (title compound)                                                                       pyrrolidine                                                                          1-[(1,9-dimethyl//acetyl]pyrrolidine                                          nmr(CDCl.sub.3) ∂ 1.77(3H),                                      2.82(2H),                                                                     3.78(3H),                                          607    488 (title compound)                                                                       piperidine                                                                           1-[(1,9-dimethyl//acetyl]piperidine                608    488 (title compound)                                                                       morpholine                                                                           1-[(1,9-dimethyl//acetyl]morpholine                                           nmr(CDCl.sub.3) ∂ 1.73(3H),                                      3.03(2H),                                                                     3.70(3H)                                           609    488 (title compound)                                                                       N-methyl-                                                                            1-methyl-4-[1,9-dimethyl//acetyl]-                                     piperazine                                                                           piperazine, ν.sub.max.sup.CHCl.sub.3 1640                                  cm.sup.-1                                          610    488 (N-ethyl analog)                                                                       pyrrolidine                                                                          1-[(9-ethyl-1-methyl//acetyl]-                                                pyrrolidine                                        611    488 (N-ethyl analog)                                                                       piperidine                                                                           1-[(9-ethyl-1-methyl//acetyl]-                                                piperidine                                         612    488 (N-propyl analog)                                                                      morpholine                                                                           1-[(1-methyl-9-propyl//acetyl]-                                               morpholine                                         613    488 (title compound)                                                                       N-piperazine-                                                                        1-(2-hydroxyethyl)-4-[1,9-dimethyl//                                   ethanol                                                                              acetyl]piperazine, γ.sub.max.sup.film                                   1625 cm.sup.-1.                                    614    492          pyrrolidine                                                                          1-[(1-methyl-9-propyl//propionyl]-                                            pyrrolidine                                        615    493          piperidine                                                                           1-[(1,9-dimethyl//propionyl]-                                                 piperidine                                         616    494          morpholine                                                                           1-[(1-methyl-9-phenethyl//propionyl]                                          morpholine                                         617    495          piperazine                                                                           1-[1-methyl-9-(3-piperidinopropyl)//                                          propionyl]piperazine                               618    496          pyrrolidine                                                                          1-{1-methyl-9-[2-(1-pyrrolidinyl)-                                            ethyl]//carbonyl}pyrrolidine                       619    501          morpholine                                                                           1-[(1-ethyl-9-methyl//acetyl]-                                                morpholine                                         620    502          N-piperazine-                                                                        1-(3-hydroxypropyl)-4-[1,9-diethyl//                                   propanol                                                                             acetyl]piperazine                                  621    505          pyrrolidine                                                                          1-[(9-methyl-1-propyl//acetyl]-                                               pyrrolidine                                        622    507          morpholine                                                                           1-[(9-allyl-1-propyll//acetyl]-                                               morpholine                                         623    509          piperidine                                                                           1-[(9-benzyl-1-isopropyl//acetyl]-                                            piperidine                                         624    511          piperazine                                                                           1-[(1,9-dipropyl-3-methyl//acetyl]-                                           piperazine                                         625    513          N-ethyl-                                                                             1-ethyl-4-[(α,1,9-trimethyl-α//                            piperazine                                                                           acetyl]piperazine                                  626    525          N-propyl-                                                                            1-propyl-4-[(1-cyclopropyl-α,β-                             piperazine                                                                           diethyl-6-ethoxy-9-(3-piperidino-                                             propyl//propionyl]piperazine                       627    566          pyrrolidine                                                                          1-[(1,9-dimethyl//butyryl]-                                                   pyrrolidine                                        628    527          N-piperazine-                                                                        9-benzyl-1-(hydroxymethyl)-4-                                          methanol                                                                             [(1-methyl//butyryl]piperazine                     629    530          morpholine                                                                           1-[(7-chloro-α,β,β,γ,.gam                               ma.,4,4-                                                                      heptacethyl-i-methyl-9-vinyl//                                                butyryl]morpholine                                 __________________________________________________________________________

                                      TABLE XIII                                  __________________________________________________________________________           NO. OF THE EXAMPLE  PRODUCT: [(PREFIX LISTED BELOW)-1,3,                      IN WHICH STARTING   4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                          MATERIAL IS         INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED     AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________    630    534          (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//acetamide                     631    534          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//acetamide                         632    534          NH.sub.3                                                                             1,9-dimethyl//acetamide                            633    534          n-C.sub.6 H.sub.13 NH.sub.2                                                          1,9-dimethyl-N-hexyl//acetamide                    634    534          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,9-dimethyl//acetamide                635    533          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//acetamide                 636    537          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//propionamide                      637    537          (C.sub.2 H.sub.5).sub.2 NH                                                           1,9-dimethyl-N,N-diethyl//propion-                                            amide                                              638    539          NH.sub.3                                                                             9-allyl-1-methyl//propionamide                     639    539          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//prpionamide               640    541          CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-(3-piperidinopropyl)//                                         carboxamide                                        641    542          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-6-hydroxy-1-propyl-                                               3,3,9-trimethyl//carboxamide                       642    544          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-ethyl//acetamide                    643    546          (C.sub.2 H.sub.5).sub.2 NH                                                           9-(2-morpholinoethyl)-N,N,1-                                                  triethyl//acetamide                                644    547          (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-ethyl-9-propargyl//                                            acetamide                                          645    548          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-propyl//acetamide                   646    550          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N-diethyl-1-propyl//                                                acetamide                                          647    557          CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-9-propyl-N,α,α                                       trimethyl//acetamide                               648    558          (CH.sub.3).sub.2 NH                                                                  6-methoxy-N,N,1,9-tetramethyl//                                               acetamide                                          649    564          (C.sub.2 H.sub.5).sub.2                                                              N,N,α,α,β,β,3-heptaethyl-                               1-methyl-                                                                     6-nitro-9-vinyl//propionamide                      650    565          (C.sub.2 H.sub.5).sub.2 NH                                                           1-cyclopropyl-6-ethoxy-N,N,α,β,9-                                  pentaethyl//propionamide                           651    566          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//butyramide                        652    567          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//butyramide                653    568          NH.sub.2                                                                             1,9-diethyl-γ,3-dimethyl//butyramide         __________________________________________________________________________

                                      TABLE XIV                                   __________________________________________________________________________           NO. OF THE EXAMPLE  PRODUCT: [(PREFIX LISTED BELOW)-1,3-                      IN WHICH STARTING   4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                          MATERIAL IS         INDOLE-1-YL)-(SUFFIX LISTED BELOW)]                EXAMPLE                                                                              PREPARED     AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________    654    533          pyrrolidine                                                                          1-[(9-allyl-1-methyl//acetyl]-                                                pyrrolidine                                        655    534          piperidine                                                                           1-[(1,9-dimethyl//acetyl]piperidine                656    535          morpholine                                                                           1-[(1-methyl-9-(2-morpholino-                                                 ethyl)//acetyl]morpholine                          657    536          pyrrolidine                                                                          1-[(1-methyl-9-propyl//propionyl]-                                            pyrrolidine                                        658    537          piperidine                                                                           1-[(1,9-dimethyl//propionyl]-                                                 piperidine                                         659    538          morpholine                                                                           1-[(1-methyl-9-propargyl//                                                    propionyl]morpholine                               660    539          piperazine                                                                           1-[9-allyl-1-methyl//propionyl]-                                              piperazine                                         661    539          N-methyl-                                                                            1-methyl-4-[9-allyl-1-methyl//                                         piperazine                                                                           propionyl]piperazine                               662    540          pyrrolidine                                                                          1-[(1,9-dimethyl//carbonyl]-                                                  pyrrolidine                                        663    541          morpholine                                                                           1-{(1-methyl-9-(3-piperidino-                                                 propyl)//carbonyl}morpholine                       664    544          morpholine                                                                           1-[(1-ethyl-9-methyl//acetyl]-                                                morpholine                                         665    547          N-piperazine-                                                                        1-(3-hydroxypropyl)-4-[(1-ethyl-                                       propanol                                                                             9-propargyl//acetyl]piperazine                     666    548          pyrrolidine                                                                          1-[(9-methyl-1-propyl//acetyl]-                                               pyrrolidine                                        667    549          morpholine                                                                           1-[(1,9-dipropyl//acetyl]-                                                    morpholine                                         668    552          piperidine                                                                           1-[(1-isopropyl-9-methyl//                                                    acetyl]piperidine                                  669    555          piperazine                                                                           1-[9-benzyl-3-methyl-1-propyl//                                               acetyl]piperazine                                  670    556          N-ethyl-                                                                             1-ethyl-4-[α,1,9-trimethyl//                                     piperazine                                                                           acetyl]piperazine                                  671    565          N-propyl-                                                                            1-propyl-4-[(1-cyclopropyl-6-                                          pyrazine                                                                             ethoxy-α,β,9-triethyl//propionyl]-                                 piperazine                                         672    566          pyrrolidine                                                                          1-[(1,9-dimethyl//butyryl]-                                                   pyrrolidine                                        673    567          N-piperazine-                                                                        1-(hydroxymethyl)-4-[(9-allyl-1-                                       methanol                                                                             methyl//butyryl]piperazine                         __________________________________________________________________________

EXAMPLE 6741,9-Dimethyl-1-[2-(Dimethylamino)Ethyl]-1,3,4,9-Tetrahydropyrano[3,4-b]Indole[I;R¹ = CH₃, R², R³, R⁴, R⁵, and R⁶ = H, R⁷ = CH₃, X = O and Y = CH₂ CH₂N(CH₃)₂ ]

A solution ofN,N,1,9-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide(12.0 g), described in Example 572, in dry tetrahydrofuran (100 ml.) isadded dropwise to a mechanically stirred mixture of lithium aluminiumhydride (5 g) in dry tetrahydrofuran (THF) (100 ml.). The mixture isheated at reflux for twenty hours under nitrogen. Water-THF (1:1, 50ml.) is added to destroy the excess hydride. The mixture is filteredthrough celite, diluted with water (300 ml.) and extracted three timeswith ether. The organic phase is dried over sodium sulfate, filtered andevaporated to dryness under reduced pressure to yield the titlecompound, nmr (CDCl₃) δ1.66 (3H), 2.70 (6H), 3.83 (3H).

The corresponding hydrochloric acid addition salt,1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrochloride, has m.p. 229°-230° C. after crystallization frommethylene dichloride-benzene.

The title compound is resolved by the use of d- and l-di-p-toluoyl-tartaric acid into the optical isomer,(-)-1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,[α]_(D) ^(CHCl).sbsp.3 = -41.5° and its corresponding (+) antipodehaving [α]_(D) ^(CHCl).sbsp.3 34.6°.

By following the procedure of Example 674 but using as starting materialan equivalent amount of one of the N-alkylated amide compounds offormula VII, described in Examples 573 to 673 instead ofN,N,1,9-tetramethyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetamide then thecorresponding N-alkylated amine compound of formula I is obtained.Examples of such compounds are listed as products in Tables XV and XVItogether with the appropriate starting material. In each case thestarting material is noted by the example in which it is prepared.

                                      TABLE XV                                    __________________________________________________________________________          NO. OF THE EXAMPLE                                                            IN WHICH STARTING                                                                         PRODUCT: (PREFIX LISTED BELOW)-                             EXAMPLE                                                                             MATERIAL IS PREPARED                                                                      1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE                       __________________________________________________________________________    675   573         1,9-dimethyl-1-[2-(methylamino)ethyl]                                         nmr (CDCl.sub.3) δ 1.10(1H), 1.66(S, 3H), 2.33                          (S,3H), corresponding hydrobromic acid                                        addition salt has m.p. 223-225° C.                   676   574         1-(2-aminoethyl)-1,9-dimethyl, ν.sub.max.sup.CHCl.sbs                      p.3 3369,                                                                     1570 cm.sup.-1                                              677   575         1,9-dimethyl-1-[2-(hexylamino)ethyl]                        678   576         1-[2-(diethylamino)ethyl]-1,9-dimethyl,                                       nmr (CDCl.sub.3) δ 0.94 (t, 6H), 1.06 (S, 3H),                          2.50 (m, 10H).                                              679   577         1-[2-(dimethylamino)ethyl]-9-ethyl-1-                                         methyl, nmr (CDCl.sub.3) δ 1.39 (3H), 1.70 (3H),                        2.73 (m, 12H), corresponding hydrochloric                                     acid addition salt has m.p. 202 - 205° C.            680   578         9-ethyl-1-methyl-1-[2-(methylamino)ethyl]                   681   579         1-(2-aminoethyl)-9-ethyl-1-methyl                           682   580         1-[2-(dimethylamino)ethyl]-1-methyl-9-                                        propyl, nmr (CDCl.sub.3), δ1.00 (t, 3H), 1.65                           (S, 3H), corresponding maleic acid                                            addition salt has m.p. 125 - 126° C.                 683   581         1-methyl-1-[2-(methylamino)ethyl]-9-propyl                  684   582         9-allyl-1-methyl-1-[2-(methylamino)ethyl]                   685   583         1-[2-(dimethylamino)ethyl]-1-methyl-9-                                        propargyl                                                   686   584         1,9-dimethyl-1-[3-(dimethylamino)propyl],                                     nmr (CDCl.sub.3) δ1.60 (3H), 2.68 (6H),                                 corresponding maleic acid addition salt                                       has m.p. 115 - 118° C.                               687   585         1,9-dimethyl-1-[3-(methylamino)propyl], nmr                                   (CDCl.sub.3) δ 1.6(3H), 2.9(3H), 3.6(3H),                               corresponding hydrochloric acid addition                                      salt has m.p. 194-196° C.                            688   586         1-[3-(diethylamino)propyl]-1,9-dimethyl                     689   587         1-(3-aminopropyl)-1-methyl-9-(3-                                              piperidinopropyl)                                           690   588         1-[3-(dimethylamino)propyl]-1-methyl-9-                                       (3-piperidinopropyl)                                        691   589         1,3-diisopropyl-1-methyl-1-(methylamino)-                                     methyl-9-propargyl                                          692   590         1-(diethylamino)methyl-6-hydroxy-1,3,3,9-                                     tetramethyl                                                 693   591         1-ethyl-9-methyl-1-[2-(methylamino)ethyl]                   694   592         9-allyl-1-[2-(diethylamino)ethyl]-1-ethyl                   695   593         1,9-bis-[2-(dimethylamino)ethyl]-1-ethyl                    696   594         9-methyl-1-[2-(methylamino)ethyl]-1-propyl                  697   595         9-allyl-1-[2-(diethylamino)ethyl]-1-propyl                  698   596         1-cyclohexyl-1-[1,1-dimethyl-2-(methyl-                                       amino)ethyl]-9-propyl                                       699   597         9-allyl-1-butyl-1-[2-(hexylamino)ethyl]                     700   598         1,9-dimethyl-1-[2-(dimethylamino)ethyl]-                                      6-methoxy, nmr (CDCl.sub.3) δ 2.60(S,3H), 3.85                          (S, 3H), corresponding maleic acid addition                                   salt has m.p. 109-111° C.                            701   599         1-ethyl-3-methyl-1-[1-methyl-2-(methyl-                                       amino)ethyl]-9-propargyl-4,4,5-tripropyl                    702   600         1-[3-(diethylamino)-1,1,2,2-tetraethyl-                                       propyl]-3-ethyl-1-methyl-6-nitro-9-phenethyl                703   601         1-cyclopropyl-1-[1,2-diethyl-3-(diethyl-                                      amino)propyl]-6-methoxy-9-vinyl                             704   602         1,9-dimethyl-1-[4-(methylamino)butyl]                       705   603         9-benzyl-1-[4-(dimethylamino)butyl]-1-                                        methyl                                                      706   604         1,9-diethyl-1-(4-amino-1-methylbutyl)                       707   605         1-[2,3-diethyl-4-(methylamino)butyl]-1,5-                                     dipropyl-3,3,9-trimethyl                                    708   606         1,9-dimethyl-1-[2-(1-pyrrolidinyl)ethyl],                                     nmr (CDCl.sub.3) δ 1.62 (s, 3H), 3.74 (s, 3H),                          m.p. of corresponding hydrochloric acid                                       addition salt, 230 - 231° C.                         709   607         1,9-dimethyl-1-(2-piperidinoethyl),                                           nmr (CDCl.sub.3) δ 1.61 (s, 3H), 2.32 (m, 6H),                          9.81 (m, 2H), m.p. of corresponding                                           hydrochloric acid addition salt, 233 - 235° C.       710   608         1,9-dimethyl-1-(2-morpholinoethyl) nmr                                        (CDCl.sub.3) δ 1.62(3H), 2.77(2H), 3.72(3H),                            hydrochloric acid addition salt has                                           m.p. 230 - 231° C.                                   711   609         1,9-dimethyl-1-[2-(4-methyl-1-piperazinyl)-                                   ethyl], nmr (CDCl.sub.3) δ1.56 (s, 3H),                                 2.22 (s, 3H), 2.3 (m, 8H), dimaleate                                          addition salt has m.p. 194 - 195° C.                 712   610         9-ethyl-1-methyl-1-[2-(1-pyrrolidinyl)-                                       ethyl]                                                      713   611         9-ethyl-1-methyl-1-(2-piperidinoethyl)                      714   612         1-methyl-1-(2-morpholinoethyl)-9-propyl                     715   613         1,9-dimethyl-1-{2-[4-(2-hydroxyethyl)-1-                                      piperazinyl]ethyl}, nmr (CDCl.sub.3) δ1.60                              (s, 3H), 3.70 (s, 3H), m.p. of correspond-                                    ing dihydrochloride salt, m.p. 219 - 220°  C.        716   614         1-methyl-9-propyl-1-[3-(1-pyrrolidinyl)-                                      propyl]                                                     717   615         1,9-dimethyl-1-(3-piperidinopropyl)                         718   616         1-methyl-1-(3-morpholinopropyl)-9-phenethyl                 719   617         1,9-bis-(3-piperazinopropyl)-1-methyl                       720   618         1-methyl-1-[(1-piperazinyl)methyl]-9-                                         [2-(1-pyrrolidinyl)ethyl]                                   721   619         1-ethyl-9-methyl-1-(2-morpholinoethyl)                      722   620         1,9-diethyl-1-{2-[4-(3-hydroxypropyl)-1-                                      piperazinyl]ethyl}                                          723   621 9-methyl-1-propyl-1-[2-(1-pyrrolidinyl)-                                              ethyl]                                                      724   622         9-allyl-1-(2-morpholinoethyl)-1-propyl                      725   623         9-benzyl-1-isopropyl-1-(2-piperidinoethyl)                  726   624         1,9-dipropyl-3-methyl-1-(2-piperazinoethyl)                 727   625         1,9-dimethyl-1-[1-methyl-2-(4-methyl-1-                                       piperazinyl)ethyl]                                          728   626         1-cyclopropyl-1-{1,2-diethyl-3-(4-propyl-                                     1-piperazinyl)propyl}-6-ethoxy-9-(3-                                          piperidinopropyl)                                           729   627         1,9-dimethyl-1-[4-(1-pyrrolidinyl)butyl]                    730   628         9-benzyl-1-{4-[4-(hydroxymethyl)-1-                                           piperazinyl]butyl}-1-methyl                                 731   629         7-chloro-4,4-diethyl-1-methyl-1-                                              (4-morpholino-1,1,2,2,3-pentaethylbutyl)-                                     9-vinyl                                                     731a  605a        1-[2-(dimethylamino)ethyl]-1,5,9-trimethyl,                                   nmr (CDCl.sub.3) δ 1.63 (s,3H), 2.20 (s,6H),                            2.67 (s,3H), 3.74 (s,3H), maleate salt                                        has m.p. 144 - 145° C.                               731b  605b        6-benzyloxy-1-[2-(dimethylamino)ethyl]-                                       9-ethyl-1-methyl, nmr (CDCl.sub.3) δ 1.38                               (t, J=7,3H), 1.62 (s,3H), 2.18 (s,6H),                                        hydrochloride salt has m.p. 216 - 217° C.            731c  605c        5-chloro-1-[2-(dimethylamino)ethyl]-1,9-di-                                   methyl, nmr (CDCl.sub.3) δ 1.63 (s,3H), 2.18                            (s,6H), 3.72 (s,3H), maleate salt has                                         m.p. 148 - 151° C.                                   731d  605         6-benzyloxy-1,9-dimethyl-1-[2-(dimethyl-                                      amino)ethyl], nmr (CDCl.sub.3) δ 1.60 (s,3H),                           2.17 (s,6H), 3.68 (s,3H), 5.12 (s, 2H),                                       hydrochloride salt has m.p. 238 - 239° C.            __________________________________________________________________________

                                      TABLE XVI                                   __________________________________________________________________________          NO. OF THE EXAMPLE                                                            IN WHICH STARTING                                                                         PRODUCT: (PREFIX LISTED BELOW)-1,3,4,9-                     EXAMPLE                                                                             MATERIAL IS PREPARED                                                                      TETRAHYDROTHIOPYRANO[3,4-b]INDOLE                           __________________________________________________________________________    732   630         1,9-dimethyl-1-[2-(dimethylamino)ethyl],                                      nmr (CDCl.sub.3) δ3.72 (s,6H), 6.40 (s,3H); the                         hydrochloric acid addition salt has m.p.                                      254 - 256° C                                         733   631         1,9-dimethyl-1-[2-(methylamino)ethyl]                       734   632         1-(2-aminoethyl)-1,9-dimethyl                               735   633         1,9-dimethyl-1-[2-(hexylamino)ethyl]                        736   634         1-[2-(diethylamino)ethyl]-1,9-dimethyl                      737   635         9-allyl-1-[2-(dimethylamino)ethyl]-1-methyl,                                  nmr (CDCl.sub.3) δ 1.79 (s, 3H), 2.18 (s, 6H),                          3.02 (m, 4H), 4.90 (m, 2H), 5.17 (m, 2H),                                     5.95 (m, 1H); corresponding hydrochloric                                      acid addition salt has m.p. 228 - 230° C                               after crystallization from ethanol.                         738   636         1,9-dimethyl-1-[3-(methylamino)propyl]                      739   637         1-[3-(diethylamino)propyl]-1,9-dimethyl                     740   638         9-allyl-1-(3-aminopropyl)-1-methyl                          741   639         9-allyl-1-[3-(dimethylamino)propyl]-1-                                        methyl                                                      742   640         1-methyl-1-[(methylamino)methyl]-9-                                           (3-piperidinopropyl)                                        743   641         1-[(diethylamino)methyl]-6-hydroxy-1-propyl-                                  3,3,9-trimethyl                                             744   642         1-ethyl-9-methyl-1-[2-(methylamino)ethyl]                   745   643         1-[2-(diethylamino)ethyl]-1-ethyl-9-                                          (2-morpholinoethyl)                                         746   644         1-[2-(dimethylamino)ethyl]-1-ethyl-9-pro-                                     pargyl                                                      747   645         9-methyl-1-[2-(methylamino)ethyl]-1-propyl                  748   646         9-allyl-1-[2-(diethylamino)ethyl]-1-propyl                  749   647         1-cyclohexyl-1-[1,1-dimethyl-2-(methyl-                                       amino)ethyl]-9-propyl                                       750   648         1,9-dimethyl-1-[2-(dimethylamino)ethyl]-                                      6-methoxy                                                   751   649         1-[3-(diethylamino)-1,1,2,2-tetramethyl-                                      propyl]-3-ethyl-6-nitro-9-vinyl                             752   650         1-cyclopropyl-1-[1,2-diethyl-3-                                               (diethylamino)propyl]-6-ethoxy-9-ethyl                      753   651         1,9-dimethyl-1-[4-(methylamino)butyl]                       754   652         9-allyl-1-[4-(dimethylamino)butyl]-1-                                         methyl                                                      755   653         1-[4-amino-(1-methylbutyl)-1,9-diethyl]-3-                                    methyl                                                      756   654         9-allyl-1-methyl-1-[2-(1-pyrrolidinyl)-                                       ethyl]                                                      757   655         1,9-dimethyl-1-(2-piperidinoethyl)                          758   656         1-methyl-1,9-bis(2-morpholinoethyl)                         759   657         1-methyl-9-propyl-1-[3-(1-pyrrolidinyl)-                                      propyl]                                                     760   658         1,9-dimethyl-1-(3-piperidinopropyl)                         761   659         1-methyl-1-(3-morpholinopropyl)-9-                                            proparyl                                                    762   660         9-allyl-1-methyl-1-(3-piperazinopropyl)                     763   661         9-allyl-1-methyl-1-[3-(4-methyl-1-                                            piperazinyl)propyl]                                         764   662         1,9-dimethyl-1-[1-pyrrolidinyl)methyl]                      765   663         1-methyl-1-(morpholinomethyl)-9-                                              (3-piperidinopropyl)                                        766   664         1-ethyl-9-methyl-1-(2-morpholinoethyl)                      767   665         1-ethyl-1-{2-[4-(3-hydroxypropyl)-1-                                          piperazinyl]ethyl}-9-propargyl                              768   666         9-methyl-1-propyl-1-[2-(1-pyrrolidinyl)-                                      ethyl]                                                      769   667         1,9-dipropyl-1-(2-morpholinoethyl)                          770   668         1-isopropyl-9-methyl-1-(2-piperidinoethyl)                  771   669         9-benzyl-3-methyl-1-(2-piperazinoethyl)-                                      1-propyl                                                    772   670         1,9-dimethyl-1-[1-methyl-2-(4-methyl-1-                                       piperazinyl)ethyl]                                          773   671         1-cyclopropyl-6-ethoxy-9-ethyl-1-[1,2-                                        diethyl-3-(4-propyl-1-piperazinyl)propyl]                   774   672         1,9-dimethyl-1-[4-(1-pyrrolidinyl)butyl]                    775   673         9-allyl-1-{4-[4-(hydroxymethyl)-1-                                            piperazinyl]butyl}-1-methyl                                 __________________________________________________________________________

EXAMPLE 7761-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-1-Carboxamide(VII, R¹ =CH₃, R², R³, R⁴, R⁵ R⁶ and R⁷ = H, X = O, and Z = CONH₂)

By following the procedure of Example 1 but using borontrifluoride-etherate as the acid catalyst and an equivalent amount ofpyruvamide instead of ethyl acetoacetate,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxamide, m.p. 188°-189° C. after recrystallization from benzene-hexane, identical with theproduct of Example 133, is obtained.

In the same manner but using an equivalent amount of the appropriatestarting material of formula II together with the appropriate α-,β-, γ-or δ-ketoamide, the products listed in Tables III and IV are obtained.For example, by using tryptophol (II; R², R³, R⁴, R⁵, R⁶ = H and X¹ =OH) and the β-ketoamide, N,N-dimethyl-acetoacetamide, in the procedureof this Example,N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,identical with the product of Example 126, is obtained.

EXAMPLE 7771-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-1-Carboxaldehyde

A mixture of the starting material, tryptophol (32.2 g, 0.2 mole),acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acidin 500 ml of benzene is refluxed for 11/2 hr. in the presence of aDean-Stark water trap. The benzene solution is washed with 5% sodiumbicarbonate, water, dried and evaporated to afford an oil. The oil issubjected to chromatography on a silica gel column using 10% ethylacetate in benzene as eluent. The acetate1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol acetate isobtained as an oil, nmr (CDCl₃) δ1.52 (S,3H), 2.08(S,3H), 4.35(2H).

This acetate is dissolved in 250 ml of methanol and stirred at roomtemperature. To this solution is added dropwise 20 ml of 10N NaOH.Hydrolysis is immediate. Most of the methanol is removed under reducedpressure, and water is added. The mixture is rendered neutral andextracted with chloroform. The chloroform extract is dried andevaporated to afford the primary alcohol,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol, m.p. 145° -147° C., nmr(CDCl₃) δ1.43 (s, 3H), 2.68 (t, J = 5.5 cps, 2H), 3.65 (d, J= 6 cps, 2H), 3.86 (t, J = 5.5 cps, 2H), after crystallization frombenzene-petroleum ether.

N,N-dicyclohexylcarbodiimide (17.36 g, 0.084 mole) is added to a cooled,stirred solution of the above primary alcohol (6.09 g, 0.028 mole) in 63ml of dimethyl sulfoxidebenzene (2:1) containing trifluoroacetic acid(1.12 ml, 0.014 mole) and pyridine (2.24 ml, 0.028 mole). The reactionis stirred at room temperature under nitrogen for 5 hr. The reactionmixture is now diluted with 600 ml of ether, followed by the dropwiseaddition of a solution of oxalic acid (7.56 g) in 21 ml of methanol.After thirty minutes, water (600 ml) is added and the insoluble materialis collected. The organic phase is washed with water (2X), 5% aqueoussodium bicarbonate (2X) and water (2X). After drying (MgSO₄) the organicphase is evaporated to yield an oil. The oil is purified bychromatography on silica gel. Elution with 10% ether in benzene affordsthe title compound as eluate, nmr (CDCl₃) δ1.59 (s,3H), 2.84 (t, J = 5.5cps, 2H), 4.15 (t, J = 5.5 cps, 2H).

EXAMPLE 778

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde,described in Example 777, is treated with an excess of dimethylamineaccording to the method of K. N. Campbell, et al., J. Amer. Chem. Soc.,70, 3868 (1948), to yield the corresponding Schiff base. Reduction ofthe latter compound with sodium borohydride according to the proceduredescribed by E. Schenker, Angew Chem., 73, 81 (1961), affords1-[(dimethylamino)methyl]1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, identical to the product of Example 317.

By following the procedures of Examples 777 and 778 in sequence, butusing as starting material in Example 777 an equivalent amount of theappropriate starting material of formula II, for example, thosedescribed in Examples 1 to 125, inclusive, and using an equivalentamount of the appropriate ketoalcohol lower alkyl ester of formula VI,described above, and in the procedure of Example 778 using anappropriate amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as definedin the first instance, then the respective compounds of formula I, forexample, those described in Example 309 (other than the title company)to 487, inclusive, are obtained.

More specifically exemplified, the use of indole-3-ethanethiol, acetonylacetate and n-hexylamine in the manner just described for the startingmaterial of formula II, the appropriate ketoalcohol lower alkyl esterand amine, respectively, yields1-[2-(hexylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano-[3,4-b]indole.

EXAMPLE 779

Oxidation of1-methyl-1,3,4,9tetrahydropyrano[3,4-b]-indole-1-carboxaldehyde,described in Example 777, with silver oxide according to the method ofDelepine and Bonnet, cited above, affords1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid, nmr(CDCl₃) δ1.79 (s, 3H), 2.83 (t, 2H), 4.17 (t, 2H), 9.20 (1H), identicalto the product obtained in Example 4.

By following the procedures of Examples 777 and 779, in sequence, butusing as starting material an equivalent amount of the appropriatestarting material of formula II, for example, those described inExamples 1 to 125, inclusive, instead of tryptophol, and using anequivalent amount of the appropriate ketoalcohol lower alkyl ester offormula VI, in which R¹ is as defined in the first instance and Z is CH₂OCOR²⁰ or Alk¹ CH₂ OCOR²⁰ wherein R²⁰ and Alk¹ are as defined in thefirst instance, then the acid compound of formula I in which R⁷ ishydrogen and Y is COOH or Alk¹ COOH wherein Alk¹ is as defined above,for example, the respective products of Examples 1 to 125, inclusive,are obtained.

More specifically exemplified, according to the procedures of Examples777 and 779, the use of tryptophol and 6-acetoxy-2-hexanone, affords1-methyl-1,3,4,9-tetrahydrothiopyrano-[3,4-b]indole-1-butyric acid,identical to the product of Example 48. Similarly, the use of tryptopholand 5-acetoxypentan-2-one affords1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid,identical to the product of Example 2.

EXAMPLE 7801-(Aminomethyl)-1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole (I, R¹ =CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ NH₂)

A solution of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-carboxaldehyde (547mg), described in Example 777, aqueous hydroxylamine hydrochloride (2.5ml of 5N) and aqueous sodium acetate (2.5 ml of 5N) and methanol (5 ml)is heated at 50° - 60° C. for 5 min. and then kept at 4° C. for 16 hr.The precipitate is collected and recrystallized from ethanol water toafford 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehydeoxime, m.p. 176° - 178° C.

The latter compound (230 mg) in dry THF (10 ml) is added dropwise to astirred mixture of lithium aluminum hydride (200 mg) in 15 ml. of THF atice bath temperature. The mixture is stirred for 1 hr., during whichtime it is allowed to come to room temperature. Excess lithium aluminumhydride is destroyed by the careful addition of H₂ O/THF(1:1). Insolublematerial is collected on a filter and the filtrate is concentrated. Theconcentrate is taken up in ether. The ether solution is dried (MgSO₄),filtered and concentrated to afford the title compound, identical withthe compound of the same name described in Example 316.

EXAMPLE 7811-Methyl-1-[3-(1-Pyrrolidinyl)propyl]-1,3,4,9-Tetrahydropyrano[3,4-b]Indole(I,R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = ##STR61##

To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene,5-chloro-2-pentanone (12 g, 0.10 M) is added. The mixture is heated inthe presence of 200 mg of p-toluene sulfonic acid and hydratedalkali-aluminum silicate (Molecular Sieves No.4). After 1 hr. ofrefluxing, 400 mg more of acid is added. After a total of 2 hr. thereaction is cooled, filtered and washed with 5% sodium bicarbonate,water and dried over sodium sulfate. Evaporation under reduced pressureaffords an oil. This oil is purified by chromatography on silica gel.Elution with benzene and concentration of the eluent gives1-(3-chloropropyl)-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole, nmr(CDCl₃) δ1.33 (3H); 1.93 (4H), 2.75 (2H).

A solution of the latter compound (250 mg, 0.9 millimoles) in 10 ml ofTHF and 1.5 ml of pyrrolidine is heated at reflux for 16 hr. The mixtureis concentrated under reduced pressure and the residue partitionedbetween 5% sodium carbonate and chloroform. The organic phase is washedwith water, dried (Na₂ SO₄), filtered and evaporated under reducedpressure to give the title compound, identical with the product ofExample 365.

By following the procedure of Example 781 but using as starting materialan equivalent amount of the appropriate starting material of formula II,for example, those described in Examples 1 to 125, inclusive, instead oftryptophol, and using an equivalent amount of the appropriate β-, γ-, orδ- haloketone of formula VI, described above, and the appropriate amineof formula HNR⁸ R⁹, described above, then the respective compounds offormula I, for example those described in Examples 309 to 487,inclusive, are obtained.

EXAMPLE 7821-[(Ethylamino)methyl]-1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole(I,R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ NHCH₃)

A mixture of tryptophol (3.86 g; II, R², R³, R⁴, R⁵, R⁶ = H and X¹ =OH)and acetamidoacetone (3.0 g), see R. H. Wileg and O. H. Borum, J. Amer.Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred andheated to reflux. Water is collected in a Dean-Stark trap. After removalof the water five drops of boron trifluoride-etherate is added and themixture refluxed 30 min. using the water-separator again. After stirringat room temperature overnight, the reaction mixture is evaporated todryness. The solid residue is dissolved in chloroform and washedsuccessively with 10% aqueous sodium bicarbonate, water, and brine. Thechloroform solution is dried over magnesium sulfate, filtered, andevaporated. The residue is crystallized from benzene to yield1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p.100° - 102° C. This product is dried under reduced pressure at 27° C.Spectroscopic and analytical data show that the compound is solvatedwith one mole of benzene which can be removed completely only bemelting. R_(f) values of the amide and tryptophol are equal.

The latter product (2.4 g) is dissolved in 80 ml of dry THF and added toa suspension of lithium aluminum hydride in 200 ml of THF.

The resultant slurry is stirred and heated to reflux for 2 hr. cooledand 2.4 g of lithium aluminum hydride is added. The mixture is thenrefluxed with stirring overnight. The reaction mixture is decomposedwith 22.4 ml of water added dropwise over 3 hr. upon stirring andcooling. Stirring is continued for 1 hr. the precipitate is separated byfiltration and the filtrate is dried (MgSO₄). Removed of the solvent byevaporatin yield the title compound, nmr (DMSO-d₆) δ1.18 (t, 3H), 1.62(s, 3H), 2.80 (t, 2H), identical to the product of Example 319.

The corresponding hydrochloric acid addition salt,1-[(ethylamino)methyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrochloride, has m.p. 242° - 243° C., after recrystallization fromisopropanol-ether.

By following the procedure of Example 782 but using as starting materialan equivalent amount of the appropriate starting material of formula II,for example, those described in Examples 1 to 125, and using anequivalent amount of an appropriate ketoamide of formula ##STR62##described above, then the respective secondary amine compounds offormula I are obtained.

EXAMPLE 783 1-Methyl-1-Nitromethyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole(VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Z = CH₂ NO₂)

To a solution of 322 mg of tryptophol (II, R², R³, R⁴, R⁵, R⁶ = H and X¹=OH) and 248 mg of the nitroketone, nitro-2-propanone, in 100 ml ofbenzene is added five drops of boron trifluoride etherate and threedrops of trifluoroacetic acid. The reaction mixture is stirred andheated at reflux under water-separator for 18 hr. The benzene solutionis cooled, washed with 10% sodium bicarbonate solution, water, saturatedbrine solution, and dried over magnesium sulfate. The solvent is removedand the residue is subjected to chromatography on silica gel. Elutionwith chloroform gives the title compound, ν_(max) ^(CHCl).sbsp.3 3450,1550cm⁻¹, nmr (CHCl₃) δ1.68 (s, 3H), 2.84 (t, 2H), 4.10 (t, 2H).

Reduction of the latter compound with lithium aluminum hydride accordingto the procedure of Example 309 affords1-(aminomethyl)-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole,identical with the product of Example 316.

By following the procedure of Example 783 but using as starting materialan equivalent amount of the appropriate starting material of formula II,for example, those described in Examples 1 to 125, and using anequivalent amount of an appropriate nitroketone of formula ##STR63##described above, then the respective primary amine compounds of formulaI are obtained.

EXAMPLE 7846-Hydroxy-1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-1-AceticAcid(VII; R¹ = CH₃, R², R³, R⁴, R⁵ and R⁷ = H, R⁶ = 6--OH, X = O, and Z= CH₂ COOH)

A mixture of6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid(5.3 g., 0.015 mole), prepared as described in Example 25, in 250 ml. ofanhydrous ethanol, and 1.1 g. of 10% palladium on carbon is stirred atroom temperature under a hydrogen atmosphere until no more hydrogen isbeing taken up by the reaction mixture. The catalyst is removed byfiltration through diatomaceous earth (Celite) and the filtrateconcentrated. The residue is recrystallized from ethanol-benzene toafford the title compound, m.p. 170° - 171° C.

The corresponding benzylamine salt is prepared by the mixing ofequimolar ethereal solutions of benzylamine and the above product. Theresulting solid is recrystallized from acetonitrile to afford6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acidbenzylamine salt, m.p. 191° - 193° C. The corresponding acetate isprepared by allowing a mixture of the title compound and a five molarexcess of acetic anhydride in pyridine solution to stand for 24 hr.Dilution of the mixture with water extraction with ether andrecrystallization of the extract residue from benzene-petroleum ether,affords6-acetoxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid,identical with the product of Example 24.

By following the procedure of this example but replacing6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acidwith an equivalent amount of6-benzyloxy-1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrochloride, described in Example 731b, then1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-6-olhydrochloride, is obtained m.p. 213° - 214° C; the corresponding freebase of the latter compound has nmr (CDCl₃) δ 1.36 (t, ν= 7 cps, 3H) 1.6(s,3H), 2.18 (s,6H). Likewise, replacement with6-benzyloxy-1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-]indolehydrochloride described in Example 731d, gives1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-olhydrochloride, m.p. 242°-244° C., corresponding free base has nmr(CDCl₃) δ 1.6 (s,3H), 2.2 (s,6H), 3.7 (s,3H).

EXAMPLE 785 1,1-Dimethyl-1,3,4,9-Tetrahydropyrano-[3,4-b]Indole (VII; R¹= CH₃, R², R³, R⁴, R⁵, R⁶, and R⁷ = H and Z = CH₃)

A solution of tryptophol (8 g, 0.05M), acetone (5 g) andp-toluenesulfonic acid (100 mg) in 100 ml of benzene containing hydratedalkali-aluminium silicate (Molecular Sieves No. 4) is heated to refluxfor 1 hr. More p-toluenesulfonic acid (100 mg) and the ketone, acetone(3 g), is added and the reflux continued for a further 1.5 hr.

The mixture is filtered and the filtrate is washed with 5% sodiumbicarbonate and water. After drying over sodium sulfate the benzene isevaporated under reduced pressure affording a solid. Chromatography ofthis solid on silica gel using 30% ethyl acetate in benzene as eluantgives a white product which is recrystallized once frombenzene-petroleum ether to give the title compound, m.p. 142° - 144° C.,nmr (CDCl₃) δ2.76 (t, J = 5.5 cps, 2H), 4.03 (t, J = 5.5 cps, 2H).

The procedure of Example 785 is followed to prepare other compounds offormula VII in which R¹, R², R³, R⁴, R⁵ R⁶ are as defined in the firstinstance, R⁷ is hydrogen and Z is lower alkyl or phenyl(lower)alkyl.Examples of such compounds are listed in Tables XVII and XVIII. In eachexample an equivalent amount of the starting material of formula IIlisted therein is used instead of the starting material of formula IIdescribed in Example 785, together with the appropriate ketone.

                                      TABLE XVII                                  __________________________________________________________________________                                                    PRODUCT: (PREFIX LISTED        EX.                                                                              STARTING MATERIAL OF FORMULA II                                                                           ##STR64##       BELOW)-1,3,4,9- TETRAHYDRO                                                    PYRANO[3,4-b]- INDOLE         __________________________________________________________________________    R.sup.2                                                                              R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                              X R.sup.1                                                                              Z                                       __________________________________________________________________________    786                                                                              H   H    H    H    H      O C.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                       1-ethyl-1-propyl              787                                                                              H   H    H    H    H      O CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1-methyl-1-propyl,m.p.                                                        91-93° C.              788                                                                              H   H    H    H    H      O C.sub.2 H.sub.5                                                                       ##STR65##                                                                              1-ethyl-1-phenethyl           789                                                                              H   H    H    H    H      O CH.sub.3                                                                              ##STR66##                                                                              1-benzyl-1-methyl,  m.p.                                                      141-145° C             790                                                                              CH.sub.3                                                                          H    H    H    H      O CH.sub.3                                                                             CH.sub.3  1,1,3-trimethyl               791                                                                              n-C.sub.3 H.sub.7                                                                 H    H    H    H      O CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1,3-dipropyl-1-methyl         792                                                                              CH.sub.3                                                                          CH.sub.3                                                                           H    H    H      O                                                                                ##STR67##                                                                           CH.sub.3  1-cyclopropyl-1,3,3-tri-                                                      ethyl                         793                                                                              C.sub.2 H.sub.5                                                                   H    C.sub.2 H.sub.5                                                                    H    H      O                                                                                ##STR68##                                                                           n-C.sub.3 H.sub.7                                                                       1-cyclohexyl-3,4-diethyl-                                                      1-propyl                     794                                                                              H   H    CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                  H      O CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1,4-dimethyl-1,4-dipropyl     795                                                                              CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           H      O CH.sub.3                                                                              ##STR69##                                                                              1-benzyl-1,3,3,4,4-penta-                                                      methyl                       796                                                                              H   H    H    H    4-CH.sub.3                                                                           O                                                                                ##STR70##                                                                           CH.sub.3  1-cyclopropyl-1,5-dimethyl                                                    a                             797                                                                              H   H    H    H    5-C.sub.2 H.sub.5                                                                    O                                                                                ##STR71##       1-cyclopentyl-6-ethyl         798                                                                              C.sub.2 H.sub.5                                                                   H    H    H    6-OCH.sub.3                                                                          O C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                         7-methoxy-1,1,3-triethyl      799                                                                              CH.sub.3                                                                          CH.sub.3                                                                           H    H    7-OC.sub.2 H.sub.5                                                                   O CH.sub.3                                                                             CH.sub.3  8-ethoxy-1,1,3,3-tetra-                                                       methyl                        800                                                                              C.sub.2 H.sub.5                                                                   H    H    H    5-NO.sub.2                                                                           O C.sub.2 H.sub.5                                                                       ##STR72##                                                                              1,3-diethyl-6-nitro-                                                          1-(3-phenylpropyl)            801                                                                              H   H    H    H    7-NO.sub.2                                                                           O CH.sub.3                                                                             CH.sub.3  1,1-dimethyl-8-nitro          802                                                                              H   H    H    CH.sub.3                                                                           6-CH.sub.3 COO                                                                       O C.sub.2 H.sub.5                                                                      CH.sub.3  7-acetoxy-1,4-dimethyl-                                                       1-ethyl                       803                                                                              n-C.sub.3 H.sub.7                                                                 n-C.sub. 3 H.sub.7                                                                 H    H    5-C.sub.2 H.sub.5 COO                                                                O                                                                                ##STR73##                                                                            ##STR74##                                                                              1-benzyl-1-cyclopropyl-                                                       3,3-dipropyl-6-propionyl-                                                     oxy                           804                                                                              H   H    H    H    4-Cl   O                                                                                ##STR75##                                                                           CH.sub.3  5-chloro-1-cyclopropyl-                                                       methyl                        805                                                                              CH.sub.3                                                                          H    H    H    6-Cl   O                                                                                ##STR76##                                                                            ##STR77##                                                                              1-benzyl-7-chloro-                                                            1-cyclohexyl-3-methyl         806                                                                              C.sub.2 H.sub.5                                                                   H    H    H    5-Br   O C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                         6-bromo-1,1,3-triethyl        807                                                                              H   H    n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  7-Br   O n-C.sub.3 H.sub.7                                                                    CH.sub.3  8-bromo-1-methyl-1,4,4-                                                       tripropyl                     808                                                                              CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           4-F    O CH.sub.3                                                                             CH.sub.3  5-fluoro-1,1,3,3,4,4-                                                         hexamethyl                    809                                                                              H   H    H    H    6-F    O                                                                                ##STR78##                                                                           n-C.sub.3 H.sub.7                                                                       1-cyclopropyl-7-fluoro-                                                       -propyl                       810                                                                              CH.sub.3                                                                          H    CH.sub.3                                                                           H    7-I    O CH.sub.3                                                                              ##STR79##                                                                              8-iodo-1-phenethyl-                                                           1,3,4-trimethyl               811                                                                              H   H    H    H    5-I    O CH.sub.3                                                                             CH.sub.3  1,1-dimethyl-6-iodo           __________________________________________________________________________

                                      TABLE XVIII                                 __________________________________________________________________________                                                    PRODUCT: (PREFIX               EX.                                                                              STARTING MATERIAL OF FORMULA II                                                                           ##STR80##       LISTED BELOW)-1,3,4,9-                                                        TETRAHYDROTHIOPYRANO-                                                         [3,4-b]INDOLE                 __________________________________________________________________________    R.sup.2 R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                           R.sup.6                                                                              X R.sup.1                                                                              Z                                       __________________________________________________________________________    812                                                                              H    H    H    H   H      S CH.sub.3                                                                             CH.sub.3  1,1-dimethyl                  813                                                                              H    H    H    H   H      S CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1-methyl-propyl               814                                                                              H    H    H    H   H      S C.sub.2 H.sub.5                                                                       ##STR81##                                                                              1-ethyl-1-phenethyl           815                                                                              H    H    H    H   H      S CH.sub.3                                                                              ##STR82##                                                                              1-benzyl-1-methyl             816                                                                              CH.sub.3                                                                           H    H    H   H      S CH.sub.3                                                                             CH.sub.3  1,1,3-trimethyl               817                                                                              n-C.sub.3 H.sub.7                                                                  H    H    H   H      S CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1,3-dipropyl-1-methyl         818                                                                              CH.sub.3                                                                           H    H    H   H      S                                                                                ##STR83##                                                                           CH.sub.3  1-cyclopropyl-1,3,3,-                                                         trimethyl                     819                                                                              C.sub.2 H.sub.5                                                                    H    C.sub.2 H.sub.5                                                                    H   H      S                                                                                ##STR84##                                                                           n-C.sub.3 H.sub.7                                                                       1-cyclohexyl-3,4-diethyl-                                                      1-propyl                     820                                                                              H    H    CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                 H      S CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1,4-dimethyl-1,4-dipropyl                                                     n                             821                                                                              CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                          H      S CH.sub.3                                                                              ##STR85##                                                                              1-benzylmethyl-1,3,3,4-                                                       4-pentamethyl                 822                                                                              H    H    H    H   4-CH.sub.3                                                                           S                                                                                ##STR86##                                                                           CH.sub.3  1-cyclopropyl-1,5-                                                            dimethyl                      823                                                                              H    H    H    H   5-C.sub.2 H.sub.5                                                                    S                                                                                ##STR87##       1-cyclopentyl-6-ethyl         824                                                                              C.sub.2 H.sub.5                                                                    H    H    H   6-OCH.sub.3                                                                          S C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                         7-methoxy-1,1,3-triethyl      825                                                                              CH.sub.3                                                                           CH.sub.3                                                                           H    H   7-OC.sub.2 H.sub.5                                                                   S CH.sub.3                                                                             CH.sub.3  8-ethoxy-1,1,3,3-                                                             tetramethyl                   826                                                                              C.sub.2 H.sub.5                                                                    H    H    H   5-NO.sub.2                                                                           S C.sub.2 H.sub.5                                                                       ##STR88##                                                                              1,3-diethyl-6-nitro-                                                          1-(3-phenylpropyl)            827                                                                              H    H    H    H   7-NO.sub.2                                                                           S CH.sub.3                                                                             CH.sub.3  1,1-dimethyl-8-nitro          828                                                                              H    H    H    CH.sub.3                                                                          6-CH.sub.3 COO                                                                       S C.sub.2 H.sub.5                                                                      CH.sub.3  7-acetoxy-1,4-dimethyl-                                                       1-ethyl                       829                                                                              n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  H    H   5-C.sub.2 H.sub.5 COO                                                                S                                                                                ##STR89##                                                                            ##STR90##                                                                              1-benzyl-1-cyclopropyl-                                                       3,3-dipropyl-6-  propionyl                                                    oxy                           830                                                                              H    H    H    H   4-Cl   S                                                                                ##STR91##                                                                           CH.sub.3  5-chloro-1-cyclopropyl-1-                                                     methyl                        831                                                                              CH.sub.3                                                                           H    H    H   6-Cl   S                                                                                ##STR92##                                                                            ##STR93##                                                                              1-benzyl-7-chloro-1-                                                          cyclohexyl-3-methyl           832                                                                              C.sub.2 H.sub.5                                                                    H    H    H   5-Br   S C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                         6-bromo-1,1,3-triethyl        833                                                                              H    H    n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                 7-Br   S n-C.sub.3 H.sub.7                                                                    CH.sub.3  8-bromo-1-methyl-1,4,4-                                                       tripropyl                     834                                                                              CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                          4-F    S CH.sub.3                                                                             CH.sub.3  5-fluoro-1,1,3,3,4,4-                                                         hexamethyl                    835                                                                              H    H    H    H   6-F    S                                                                                ##STR94##                                                                           n-C.sub.3 H.sub.7                                                                       1-cyclopropyl-7-fluoro-                                                       1-propyl                      836                                                                              CH.sub.3                                                                           H    CH.sub.3                                                                           H   7-I    S CH.sub.3                                                                              ##STR95##                                                                              8-iodo-1-phenethyl-                                                           1,3,4-trimethyl               837                                                                              H    H    H    H   5-I    S CH.sub.3                                                                             CH.sub.3  1,1-dimethyl-6-iodo           __________________________________________________________________________

EXAMPLE 8381,1-Dimethyl-9-[2-(Dimethylamino)ethyl]-1,3,4,9-Tetrahydropyrano[3,4-b]Indole(I; R¹ and Y = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, and R⁷ = CH₂ CH₂ N(CH₃)₂]

To 4.2 g. of a 50% dispersion of sodium hydride in 20 ml. ofdimethylformamide is added a solution of 7 g. of1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, described in Example785, in 20 ml. of dimethylformamide. The addition is made dropwise atroom temperature while stirring vigorously. The mixture is heated for 1hr. at 40° C. Then an excess of the organic halide, dimethylaminoethylchloride (free base obtained from 15 g. of the hydrochloride) is addedand stirring continued at 40° C. overnight.

The reaction mixture is poured into ice-water, acidified with 6NHCl andwashed with ether. The aqueous phase is rendered alkaline with 10% NaOHand extracted with benzene. The organic phase is washed with water,dried over sodium sulfate, and evaporated under reduced pressure toyield the title compound, nmr (CDCl₃) δ1.63 (6H), 2.36 (6H), 2.79 (m,4H), 4.10 (m, 4H), 7.18 (m, 4H).

The corresponding hydrochloric acid addition salt,1,1-dimethyl-9-[(2-dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano-[3,4-b]indolehydrochloride, has m.p. 198° - 200° C., after crystalliztion frommethanol-ether.

The procedure of Example 838 is followed to prepare other compounds offormula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in thefirst instance, R⁷ is aminoalkyl as defined above and Y is lower alkylor phenyl(lower)alkyl. Examples of such compounds are listed in TablesXIX and XX. In each example an equivalent amount of the appropriatestarting material of formula VII in which R¹, R², R³, R⁴, R⁵, R⁶ are asdefined in the first instance, R⁷ is hydrogen and Z is lower alkyl orphenyl(lower)alkyl, described in Examples 785 to 837, is used in placeof 1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole if required. Ineach case the starting material of formula VII is noted by the examplein which it is prepared.

                                      TABLE XIX                                   __________________________________________________________________________        NO. OF THE                                                                    EXAMPLE IN                                                                    WHICH STARTING            PRODUCT: (PREFIX LISTED BELOW)-                     MATERIAL IS                                                                              ORGANIC        1,3,4,9-TETRAHYDROPYRANO-                       EX. PREPARED   HALIDE         [3,4-b]INDOLE                                   __________________________________________________________________________    839 785        (CH.sub.3).sub.2 N(CH.sub.2).sub.3 Cl                                                        1,1-dimethyl-9-[3-(dimethyl-                                                  amino)propyl], nmr (CDCl.sub.3)                                               δ1.62 (6H), 2.00 (m, 2H), 2.25                                          (6H), corresponding hydrochloric                                              acid addition salt has m.p.                                                   201 - 203° C.                            840 785        CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                               1,1-dimethyl-9-[2-(methylamino)-                                              ethyl]                                          841 785        i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      1,1-dimethyl-9-[2-(isopropyl-                                                 amino)ethyl]                                    842 786        NH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 Br                                              9-(3-amino-2,2-dimethylethyl)-                                                1-ethyl-1-propyl                                843 787        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        9-[2-(dimethylamino)ethyl]-1-                                                 methyl-1-propyl,ν.sub.max.sup.CHCl.sbsp.3                                   2960,                                                                        1470, 1085 cm.sup.-1, maleate salt                                            has m.p. 144- 147°C.                     844 788        C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                        1-ethyl-9-[3-(ethylamino)propyl] -                                            1-phenethyl                                     845 789        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-benzyl-9-[2-(dimethylamino)-                                                ethyl]-1-methyl, nmr (CDCl.sub.3)                                             δ1.55 (s, 3H), 2.92 (6H), 3.95                                          (2H), corresponding hydrochloric                                              acid addition salt has m.p.                                                   218 - 220° C.                            846 789        CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                               1-benzyl-1-methyl-9-[2-(methyl-                                               amino)ethyl]                                    847 789        NH.sub.2 (CH.sub.2).sub.3 Cl                                                                 9-(4-aminobutyl)-1-benzyl-1-                                                  methyl                                          848 790        (CH.sub.3).sub.2 NCH.sub.2 [CH(CH.sub.3)].sub.2 Cl                                           9-[1,2-dimethyl-3-(dimethyl-                                                  amino)propyl]1,1,3-trimethyl                    849 791        (C.sub.2 H.sub.5).sub.2 NCH(C.sub.2 H.sub.5)CH.sub.2                                         9-[2-(diethylamino)-2-                                                        ethylethyl]-1,3-dipropyl-1-                                                   methyl                                          850 792        CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                               1-cyclopropyl-9-[3-(methyl-                                                   amino)propyl]-1,3,3-trimethyl                   851 793        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-cyclohexyl-3,4-diethyl-                                                     9-[2-(dimethylamino)ethyl]-                                                   1-propyl                                        852 794        (n-C.sub.3 H.sub.7).sub.2 N(CH.sub.2).sub.3 Cl                                               1,4-dimethyl-1,4-dipropyl-9-                                                  [3-(dipropylamino)propyl]                       853 795        (CH.sub.3 ).sub.2 NCH(n-C.sub.3 H.sub.7)CH.sub.2 Cl                                          1-benzyl-9-[2-(dimethylamino)-                                                2-propylethyl]-1,3,3,4,4-                                                     pentamethyl                                     854 796        (CH.sub.3).sub.2 N[CH(n-C.sub.3 H.sub.7)].sub.3 CH.sub.2                      Cl             1-cyclopropyl-1,5-dimethyl-9-                                                 [4-(dimethylamino)-2,3,4-                                                     tripropylbutyl]                                 855 797        (C.sub.2 H.sub.5).sub.2 N(CH.sub.2).sub.2 Cl                                                 1-cyclopentyl-9-[2-(diethyl-                                                  amino)ethyl]-6-ethyl                            856 798        CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                               7-methoxy-9-[3-(methylamino)-                                                 propyl]-1,1,3-triethyl                          857 799        n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      8-ethoxy-9-[2-(propylamino)-                                                  ethyl]-1,1,3,3-tetramethyl                      858 800        i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      1,3-diethyl-9-[2-(isopropyl-                                                  amino)ethyl]-6-nitro-1-                                                       (3-phenylpropyl)                                859 801        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1,1-dimethyl-9-[2-(dimethyl-                                                  amino)ethyl]-8-nitro                            860 802        C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                        7-acetoxy-1,4-dimethyl-1-ethyl-                                               9-[3-(ethylamino)propyl]                        861 803        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-benzyl-1-cyclopropyl-9-[2-                                                  (dimethylamino)ethyl-3,3-                                                     dipropyl-6-propionyloxy]                        862 804        n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.3 Cl                                                      5-chloro-1-cyclopropyl-1-                                                     methyl-9-[3-(propylamino)-                                                    propyl]                                         863 805        1-(3-chloropropyl)-                                                                          1-benzyl-7-chloro-1-cyclohexyl-                                pyrrolidine    3-methyl-9-[3-(1-pyrrolidinyl)-                                               propyl]                                         864 806        1-(2-chloroethyl)-                                                                           6-bromo-9-(2-piperidinoethyl)-                                 piperidine     1,1,3-triethyl                                  865 807        4-(2-chloroethyl)-                                                                           8-bromo-1-methyl-9-(2-morpholino-                              morpoline      ethyl)-1,4,4-tripropyl                          866 808        1-(3-chloropropyl)-                                                                          5-fluoro-1,1,3,3,4,4-hexamethyl-                               piperazine     9-(piperazinopropyl)                            867 809        1-(3-chloroethyl)-4-                                                                         1-cyclopropyl-7-fluoro-9-                                      methylpiperazine                                                                             [2-(4-methyl-1-piperazinyl)-                                                  ethyl]-1-propyl                                 868 810        1-(2-chloroethyl)-4-                                                                         9-{2-[4-(hydroxyethyl)-1-                                      (hydroxyethyl)piperazine                                                                     piperazinyl]ethyl}-8-iodo-1-                                                  phenethyl-1,3,4-trimethyl                       869 811        1-(2-chloroethyl)-                                                                           1,1-dimethyl-6-iodo-9-[2-(1-                                   pyrrolidine    pyrrolidinyl)ethyl]                             870 785        1-(3-chloropropyl)-                                                                          1,1-dimethyl-9-(3-piperidino-                                  piperidine     propyl)                                         871 785        4-(4-chlorobutyl)-                                                                           1,1-dimethyl-9-(4-morpholino-                                  morpholine     butyl)                                          872 789        1-(4-chlorobutyl)-                                                                           9-[4-(4-methyl-1-piperazinyl)-                                 4-methylpiperazine                                                                           butyl]                                          873 789        1-(2-chloroethyl)-4-                                                                         1-benzyl-9-{2-[4-(hydroxypropyl)-                              (3-hydroxypropyl)-                                                                           1-piperazinyl]ethyl}-1-methyl                                  piperazine                                                     __________________________________________________________________________

                                      TABLE XX                                    __________________________________________________________________________        NO. OF                                                                        EXAMPLE IN                                                                    WHICH STARTING          PRODUCT:                                              MATERIAL IS                                                                            ORGANIC        (PREFIX LISTED BELOW)-1,3,4,9-                    EX. PREPARED HALIDE         TETRAHYDROTHIOPYRANO[3,4-b]INDOLE                 __________________________________________________________________________    874 812      (CH.sub.3).sub.2 N(CH.sub.2).sub.3 Cl                                                        1,1-dimethyl-9-[3-(dimethyl-                                                  amino)propyl]                                     875 812      CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                               1,1-dimethyl-9-[2-(methylamino)-                                              ethyl]                                            876 812      i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      1,1-dimethyl-9-[2-(isopropyl-                                                 amino)ethyl]                                      877 812      NH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 Br                                              9-(3-amino-2,2-dimethylethyl)-                                                1,1-dimethyl                                      878 813      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        9-[2-(dimethylamino)ethyl]-                                                   1-methyl-1-propyl                                 879 814      C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                        1-ethyl-9-[3-(ethylamino)propyl]-                                             1-phenethyl                                       880 815      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-benzyl-9-[2-(dimethylamino)-                                                ethyl]-1-methyl                                   881 815      CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                               1-benzyl-1-methyl-9-[2-(methyl-                                               amino)ethyl]                                      882 815      NH.sub.2 (CH.sub.2).sub.3 Cl                                                                 9-(4-aminobutyl)-1-benzyl-1-                                                  methyl                                            883 816      (CH.sub.3).sub.2 NCH.sub.2 [CH(CH.sub.3)].sub.2 Cl                                           9-[1,2-dimethyl-3-(dimethyl-                                                  amino)propyl]-1,1,3-trimethyl                     884 817      (C.sub.2 H.sub.5).sub.2 NCH(C.sub.2 H.sub.5)CH.sub.2                                         9-[2-(diethylamino)-2-ethyl-                                                  ethyl]-1,3-dipropyl-1-methyl                      885 818      CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                               1-cyclopropyl-9-[3-(methyl-                                                   amino)propyl]-1,3,3-trimethyl                     886 819      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-cyclohexyl-3,4-diethyl-9-                                                   [2-(dimethylamino)ethyl]-1-                                                   propyl                                            887 820      (n-C.sub.3 H.sub.7).sub.2 N(CH.sub.2).sub.3 Cl                                               1,4-dimethyl-1,4-dipropyl-9-                                                  [3-(dipropylamino)propyl]                         888 821      (CH.sub.3).sub.2 NCH(n-C.sub.3 H.sub.7)CH.sub.2 Cl                                           1-benzyl-9-[2-(dimethylamino)-                                                2-propylethyl]-1,3,3,4,4-                                                     pentamethyl                                       889 822      (CH.sub.3).sub.2 N[CH(n-C.sub.3 H.sub.7)].sub.3 CH.sub.2                                     1-cyclopropyl-1,5-dimethyl-9-                                                 [4-(dimethylamino)-2,3,4-                                                     tripropylbutyl]                                   890 823      (C.sub.2 H.sub.5).sub.2 N(CH.sub.2).sub.2 Cl                                                 1-cyclopentyl-9-[2-(diethyl-                                                  amino)ethyl]-6-ethyl                              891 824      CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                               7-methoxy-9-[3-(methylamino)-                                                 propyl]-1,1,3-triethyl                            892 825      n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      8-ethoxy-9-[2-(propylamino)-                                                  ethyl]-1,1,3,3-tetramethyl                        893 826      i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      1,3-diethyl-9-[2-(isopropyl-                                                  amino)ethyl]-6-nitro-1-(3-                                                    phenylpropyl)                                     894 827      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1,1-dimethyl-9-[2-(dimethyl-                                                  amino)ethyl]-8-nitro                              895 828      C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                        7-acetoxy-1,4-dimethyl-1-                                                     ethyl-9-[3-(ethylamino)propyl]                    896 829      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-benzyl-1-cyclopropyl-9-                                                     [2-(dimethylamino)ethyl]-3,3-                                                 dipropyl-6-propionyloxy                           897 830      n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.3 Cl                                                      5-chloro-1-cyclopropyl-1-methyl-                                              9-[3-(propylamino)propyl]                         898 831      1-(3-chloropropyl)-                                                                          1-benzyl-7-chloro-1-cyclohexyl-                                pyrrolidine    3-methyl-9-[3-(1-pyrrolidinyl)-                                               propyl]                                           899 832      1-(2-chloroethyl)-                                                                           6-bromo-9-(2-piperidinoethyl)-                                 piperidine     1,1,3-triethyl                                    900 833      4-(2-chloroethyl)-                                                                           8-bromo-1-methyl-9-(2-morpholino-                              morpholine     ethyl)-1,4,4-tripropyl                            901 834      1-(3-chloropropyl)-                                                                          5-fluoro-1,1,3,3,4,4-hexamethyl-                               piperazine     9-(piperazinopropyl)                              902 835      1-(3-chloroethyl)-                                                                           1-cyclopropyl-7-fluoro-9-                                      4-methylpiperazine                                                                           [2-(4-methyl-1-piperazinyl)-                                                  ethyl]-1-propyl                                   903 836      1-(2-chloroethyl)-                                                                           9-{2-[4-(hydroxyethyl)-1-                                      4-(hydroxyethyl)-                                                                            piperazinyl]ethyl]-8-iodo                                      piperazine     1-phenethyl-1,3,4-trimethyl                       904 837      1-(2-chloroethyl)-                                                                           1,1-dimethyl-6-iodo-9-[2-(1-                                   pyrrolidine    pyrrolidinyl)ethyl]                               905 812      1-(3-chloropropyl)-                                                                          1,1-dimethyl-9-(3-piperidino-                                  piperidine     propyl)                                           906 812      4-(4-chlorobutyl)-                                                                           1,1-dimethyl-9-(4-morpholino-                                  morpholine     butyl)                                            907 815      1-(4-chlorobutyl)-                                                                           1-benzyl-1-methyl-9-[4-(4-                                     4-methylpiperazine                                                                           methyl-1-piperazinyl)butyl]                       908 815      1-(2-chloroethyl)-                                                                           1-benzyl-9-{2-[4-(hydroxypropyl)-                              4-(3-hydroxypropyl)-                                                                         1-piperazinyl]ethyl}-1-methyl                                  piperazine                                                       __________________________________________________________________________

EXAMPLE 9091,1-Dimethyl-9-[2-(Dimethylamino)ethyl]-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-6-ol[I. R¹ and Y =CH₃, R², R³, R⁴ and R⁵ = H, R⁶ = OH and R⁷ =CH₂ CH₂N(CH₃)₂ ]

5-Benzyloxy-3-tryptophol (II; R², R³, R⁴ and R⁵ = H, R⁶ = 5-benzyloxyand X¹ = OH), m.p. 93° - 95° C., is prepared by lithium aluminum hydridereduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Pat. No.778,823) according to the procedure of Example 309. Subsequent treatmentof 5-benzyloxy-3-tryptophol with the ketone, acetone, according to theprocedure of Example 785 affords6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VII; R¹M CH₃), nmr (CDCl₃) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H),6.67- 7.83 (9H). The latter compound is then N-alkylated with theorganic halide, dimethylaminoethyl chloride, according to the procedureof Example 838 to afford6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,which on treatment with hydrochloric acid gives the correspondinghydrochloric acid addition salt thereof, m.p. 209° C.

The latter compound,6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrochloride (11.5 g., 0.028M) in 600 ml. of absolute ethanol and 600mg of 10% palladium on carbon is stirred at room temperature under ahydrogen atmosphere for 22 hr. until no more hydrogen is taken up by thereaction. The catalyst is collected on celite and the filtrateconcentrated to afford the corresponding hydrochloric acid addition saltof the title compound, m.p. 225° - 228° C., after recrystallization fromethanol-ether.

The title compound [free base, nmr (CDCl₃) δ1.61 (6H), 2.57 (t, J = 5cps, 2H), 3.86 (t, J = 5 cps, 2H)] is obtained by decomposing thehydrochloric acid addition salt, for example, by washing a chloroformsolution of the salt with 10% sodium hydroxide solution and evaporatingthe solvent.

By replacing 5-benzyloxy-3-tryptophol with an equivalent amount of7-benzyloxy-3-tryptophol in the procedure of this example,1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole-8-olis obtained.

EXAMPLE 9101-(2-Aminoethyl)-1-Methyl-1,3,4,9-Tetrahydropyrano-[3,4-b]Indole (I; R¹= CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ NH₂)

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (20.0 g.,0.817 mole), described in Example 126, is dissolved in dry methylenechloride (400 ml) and freshly prepared triethyloxonium fluoroborate(17.00 g., 0.894 mole) is added in one portion to the solution. Thereaction mixture is stirred at room temperature for 2 hr.. The methylenechloride solution is washed with cold 30% aqueous potassium carbonatefollowed by brine and the dried organic layer is concentrated underreduced pressure. The residue is dissolved in ether (150 ml.). Thesolution is filtered and crystallization proceeds at room temperature toaffordethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetimidate, m.p.139.5° - 141° C.

The latter compound (4.79 g., 0.0176 mole) dissolved in dry THF (100ml.) is added dropwise to a stirred and ice-cooled suspension of lithiumaluminum hydride (1.75 g., 0.046 mole) in THF (50 ml.). The reactionmixture is stirred overnight at room temperature and then dilute sodiumhydroxide is added dropwise to decompose excess hydride. The precepitateis collected by filtration and the filtrate is concentrated underreduced pressure thus affording a residue which is extracted withmethylene chloride. The organic layers are washed with brine, dried(MgSO₄) and concentration of the solvent and crystallization from etheraffords the title compound, m.p. 80° - 84° C., ν_(max) ^(CHCl).sbsp.33455, 3280 cm⁻¹, identical with the compound of the same name describedin Example 309.

EXAMPLE 9111-[2-(Dimethylamino)ethyl]-9-Ethyl-1-Methyl-1,3,4,9-Tetrahydrothiopyrano[3,4-b]Indole[I; R¹ = CH₃, R², R³, R⁴, R⁵, and R⁶ = H,R⁷ = C₂ H₅, X = S and Y = CH₂CH₂ N(CH₃)₂ ]

The compound of formula I in which R⁷ = H and Y =amino(lower)alkyl,1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole(822 mg), described in Example 398, is dissolved in 15 ml of DMF and 15ml of benzene. To remove all possible traces of water, a portion of thisbenzene is distilled. After cooling to 0° C, 140 mg of sodium hydride(54% suspension in mineral oil) is added, and the mixture stirred for 15min. Alkylation is accomplished by addition of 350 mg of ethyl bromideand stirring the reaction mixture at 0° C for 20 min. The resultingsuspension is poured onto cracked ice, extracted with chloroform, theorganic layer washed repeatedly with water and evaporated.Chromatography of the residue on silica gel (20 g) usingchloroform-methanol (0-10%) affords the title compound, which aftercrystallization from ether hexane has m.p. 86° - 88° C., ν_(max).sup.CHCl.sbsp.3 2820, 2765, 1600, 1568, 1537 cm⁻¹, nmr (CDCl₃) δ2.20 (s,6H), 2.30 (m, 4H).

The corresponding hydrochloric acid addition salt of the title compound,1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indolehydrochloride, has m.p. 220° - 222° C.

By following the procedure of Example 911 and using an appropriatecompound of formula I in which R⁷ is hydrogen and Y is anamino(lower)alkyl, for instance those described in Examples 309 to 487,together with the appropriate organic halide, then other compounds offormula I in which R⁷ is lower alkyl, lower alkenyl, propargyl,phenyl(lower)alkyl or amino(lower)alkyl are obtained.

For example, the use of the same compound of formula I as described inExample 911 with an equivalent amount of methyl bromide, instead ofethyl bromide, in the procedure of Example 911 gives1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole,nmr (CHCl₃) δ3.72 (s, 6H), 6.40 (s, 3H), identical to the product ofExample 732. The corresponding hydrochloric acid addition salt of thislatter compound,1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indolehydrochloride has m.p. 244° - 246° C.

Likewise, the use of the same compound of formula I as described inExample 911 with an equivalent amount of propyl bromide, instead ofethyl bromide, gives1-[2-(dimethylamino)ethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]-indole,nmr (CHCl₃) δ1.03(t, 3H), 1.83(S,3H), 2.22(S,6H), 4.14(m, 2H), 7.22(m,4H); corresponding hydrochloric acid addition salt has m.p. 243°-245° C.

EXAMPLE 9121-[(2-Dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole[ I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ CH₂(N(CH₃)₂ ]

To a solution of p-toluenesulfonic acid (2.28 g) in toluene (40 ml), thestarting material of formula II, tryptophol (1.61 g), and theaminoketone, 4-(dimethylamino)-2-butanone (1.27 g) are added. Themixture is evaporated under reduced pressure and the residue stirredunder nitrogen at 130° C (bath temperature) for 45 min.. The mixture iscooled, water (20 ml) added and the mixture extracted with toluene. Thetoluene extract is washed with 5% sulfuric acid (5 ml) and with water (5ml). The aqueous layer containing a dark heavy oil is combined with theaqueous washes. Conc. NH₄ OH (10 ml) is added and the mixture extractedwith toluene (10 ml and 2 × 5 ml). The combined toluene solution iswashed with water (2 × 5 ml), dried (Na₂ SO₄), treated with charcoal andevaporated under reduced pressure. The residue is recrystallized fromether to afford the pure title compound, identical to the product of thesame name described in Example 309.

1,9-Dimethyl-1-[2-(dimethylamino)]-1,3,4,9-tetrahydropyrano[3,4-b]indole[ I; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵, and R⁶ = H, X = O and Y = CH₂ CH₂N(CH₃)₂ ]

To a mixture of the starting material of formula II, N-methyltryptophol(0.50 g), and the aminoketone, 4-dimethylamino-2-butanone (0.363 g),p-toluenesulfonic acid (0.650 g) is added in portions and the mixturestirred under nitrogen at 130° C for 11/2 hr. After cooling water isadded (10 ml) and the mixture is extracted with toluene (2 × 5 ml). Thecombined toluene solution is backwashed with water and discarded. Theaqueous phase, containing a heavy brown oil, is made alkaline with conc.ammonium hydroxide (10 ml) and extracted with benzene (3 × 10 ml). Thecombined benzene extract is washed with water (2 × 10 ml), dried (Na₂SO₄), treated with charcoal and evaporated under reduced pressure toyield the title compound, identical to the product of the same namedescribed in Example 674.

EXAMPLE 9141,9-Dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole[ I; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X = S and Y = CH₂ CH₂N(CH₃)₂ ]

A mixture of the starting material of formula II,1-methylindole-3-ethanethiol (0.75 g), 4-dimethylamino-2-butanonehydrochloride (0.72 g), toluene (ca. 1 ml) and p-toluenesulfonic acid(1.00 g), is stirred under nitrogen at 125° C for 1/2 hr. After cooling,water (20 ml) and conc. hydrochloric acid (0.5 ml) are added and themixture is then extracted with toluene (3 ×0 10 ml). The combinedtoluene solution is backwashed with water. The aqueous phase containinga brown oil is rendered alkaline with conc. NH₄ OH and extracted withtoluene (3 × 15 ml). The combined toluene solution is washed with water,dried (Na₂ SO₄), treated with charcoal and evaporated under reducedpressure to yield the title compound, identical to the product of thesame name described in Example 732.

EXAMPLE 915 1-[2-(Dimethylamino)ethyl] 9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole [1; R¹ ═ CH₃, R², R³,R⁴, R⁵, and R⁶ = H, R⁷ = C₂ H₅, X = S and Y = CH₂ CH₂ N(CH₃)₂ ]

To a stirred solution of p-toluenesulfonic acid monohydrate (57.0 g) intoluene (400 ml) at 80° C. under nitrogen, the aminoketone,4-(dimethylamino)-2-butanone (13.8 g), is added. Thereafter, thestarting material of formula II, sodium 1-ethylindole-3-ethylthiosulfate (30.7 g), prepared from 1-ethylindole-3-ethanol according tothe procedure of Suvorov and Buyanov, cited above, is added portionwiseover a period of 5 minutes. The mixture is maintained at 80° C. for 11/4hr. with stirring then cooled and diluted with 20% sodium hydroxide (66ml) followed by water (100 ml) and extracted with toluene. The tolueneextract is washed with 20% sulfuric acid (5 × 30 ml) and with water (5 ×30 ml). The combined aqueous phases plus solid precipitating therefromare rendered alkaline with 20% sodium hydroxide and then extracted withtoluene (4 × 50 ml). The combined toluene solution is washed with water,dried (Na₂ SO.sub. 4), and evaporated. The residue is recrystallizedfrom ether-hexane to give the title compound, identical to the productof Example 911. The corresponding hydrochloric acid addition salt of thetitle compound has m.p, 225°-227° C. after recrystallization fromisopropanol.

In the same manner but using an equivalent amount of potassium1-ethylindole-3-ethyl thiosulfate the title compound is also obtained.

By following the procedure of Examples 912, 913, 914 or 915 and using anappropriate starting material of formula II together with theappropriate aminoketone, then other compounds of formula I, for example,those described in Examples 309- 487 and 675- 775, are obtained.

EXAMPLE 9164'-Chloro-2-{methyl[2-(1,3,4,9-tetrahydro-1,9-dimethylpyrano[3,4-b]indole-1-yl)ethyl]amino}-acetophenone[I,R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X=O and Y=CH₂ CH₂N(CH₃)(p-chlorophenacyl)]

1,9-Dimethyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrobromide (2.0 g), described in Example 675, and2-bromo-4'-chloro-acetophenone (1.37 g) are dissolved in benzene (10ml). A solution of sodium hydrogen carbonate (1.2 g) and sodium sulfite(0.06 g) in water (5 ml) are added. The reaction mixture is stirred atroom temperature for 3 hr. The aqueous phase is separated and discarded.The organic phase is washed with 0.5 ml or 2N HCl, with water and dried(Na₂ SO₄). After filtration, 2.6 ml of a 2.3 M solution of hydrogenchloride in ether is added. The resulting gummy material is crystallizedfrom methanol and ether to afford the hydrochloric acid addition salt ofthe title compound, mp. 199° - 205° C (dec.).

Conversion of the latter salt to its free base is achieved washing achloroform solution of the salt with 5% NaOH solution. Subsequentconcentration of the chloroform gives the title compound as the freebase, nmr (CDCl₃)δ 1.6(s,3H), 2.3 (s,3H), 3.65 (s,2H), 3.7 (s,3H).

By replacing1,9-dimethyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrobromide with9-ethyl-1-methyl-1-[2-(methylamino(ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indolehydrochloride, described in Example 917,4'-chloro-2-{[2-(9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)ethyl]methylamino}acetophenone,nmr (CDCl₃)δ 1.40 (t, J = 7.5 Hz, 3H), 1.80 (s, 3H), 2.35 (s, 3H) isobtained; the hydrochloride addition salt of the latter compound hasm.p. 175°- 177° C.

EXAMPLE 9179-Ethyl-1-methyl-1-[2-(methylamiono)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole (I; R¹ =CH₃, R², R³, R⁴, R⁵ and R⁶ =H, R⁷ = C₂ H₅, X=S andY=CH₂ CH₂ NHCH₃)

A mixture of sodium 2-[(1-ethyl-indol-3-yl)ethyl]thiosulfate (12 g)4-(formylamino)-2-butanone (6 g), described by H. Bredereck, et al.,Chem. Ber., 2423 (1960), toluene (30 ml) and boron trifluoride-etherate(20 ml) is heated at 80° for 4 hr. After cooling, 150 ml of chloroformand 100 ml of saturated sodium bicarbonate are added. The resultantmixture is stirred until the precipitated solids dissolve. The organicphase is separated, washed with water, and concentrated. The residue ispurified by chromatography on silica gel, using chloroform andchloroform-methanol (100 : 3) as elements. Combination of majorfractions gives the N-formyl derivative,9-ethyl-1-methyl-1-[2-(formylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, ν_(max) ^(CHCl).sbsp.3 3410, 1680 cm⁻¹, nmr (CDCl₃) δ1.38(t, J=7, 3H), 1.82 (s, 3H), 2.20 (m, 2H), 3.00 (m, 6H), 4.31 (q, J=7,2H), 6.00 (broad, 1H), 7.22 (m, 4H), 7.98 (d, J=2, 1H).

The latter compound (3 g) in 40 ml of dry ether is added to a stirredsuspension of lithium aluminium hydride (0.7 g) in 40 ml of the samesolvent. The reaction mixture is heated at reflux for 3 hr., decomposedwith 4 ml of 30% aqueous solution of sodium-potassium tartrate, andfiltered. The filter cake is washed with tetrahydrofuran and thefiltrate dried (MgSO₄). Usual work-up afforded the title compound as anoil, nmr (DMSO-d₆) 1.32 (t, J=7, 3H), 1.78 (s, 3H), 7.2 (m, 3H).

The hydrochloric acid addition salt of the title compound has mp259°-261° C after recrystallization from isopropanol-methanol (9 : 1).

This example is a specific embodiment of preparation and conversion ofintermediates of formula VII (2=Alk NR⁸ COR²¹), see also Example 782.

EXAMPLE 9189-Ethyl-1-methyl-1-(2-aminoethyl)-1,3,4,9-tetrahydro-thiopyrano[3,4-b]indole(I; R¹ =CH₃, R², R³, R⁴, R⁵ and R⁶ =H, R⁷ =C₂ H₅, X=S and Y=CH₂ CH₂ NH₂)(t,J=

The N-formyl compound described in Example 917 is hydrolyzed by boilingthe compound (1.0 g) in 10 ml of conc. HCl in 10 ml of methanol for 24hr. The reaction mixture is concentrated under reduced pressure. Theaqueous residue is washed with ether, and then rendered basic with 10%NaOH. Extraction with ether affords9-ethyl-1-methyl-1-(2-aminoethyl)-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole. nmr (CDCl₃) δ 1.40 (t, J=7, 3H), 1.82 (s,3H), 1.90 (s,exchangeable, 2H), 4.31 (q,J=7, 2H). Basic hydrolysis (10% NaOH inmethanol) of the above N-formyl compound gave product identical with thepreceeding product.

The hydrochloric acid addition salt of the latter compound has mp.257° - 258° C after recrystallization from isopropanol ether.

In the same manner as described in the preceding Examples 1 to 784inclusive and 910 to 918 but replacing the starting material of formulaII with the corresponding starting material of formula IIa, thepyrano[4,3-b]indole and thiopyrano[ 4,3-b]indole derivatives of formulaIa, corresponding to the pyrano[ 3,4-b]indole and thiopyrano[3,4-b]indole derivatives of formula I, described in these precedingexamples, are obtained. This latter aspect of this invention isillustrated further in the following Examples 919 to 921.

EXAMPLE 919 1,5-Dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-aceticacid (VIIa; R¹ and R⁷ =C₃, R², R³, R⁴, R⁵ and R⁶ = H, X=O and Z=CH₂COOH)

The compound of formula VI, ethyl acetoacetate (6.5 g), is added to astirred suspension of aluminum chloride (2.0 g) in anhydrous toluene (60ml) at 60° . The mixture is stirred until solution is complete (c.a. 10min.). 2-(1-Methylindole)ethanol (IIa, R², R³, R⁴, R⁵ and R⁶ = CH₃ andX¹ =OH, 8.7 g) in toluene (60 ml) is added dropwise during 40 min. Themixture is stirred for 1 hr at 60° and then cooled to 10° C and treatedwith water (60 ml). The toluene layer is washed with water, dried andevaporated to dryness, the residue is crystallized from ethanol to givethe pure ethyl ester of the title compound, m.p. 136° -138° C.

The ester is hydrolyzed with aqueous ethanol-sodium hydroxide to givethe crude acid which crystallized from toluene to give the pure titleproduct, m.p. 181°-112° C.

1Methylindole-2-ethanyl[nmr(CDCl₃)δ 2.63, 2.88, 3.55, and 6.12] used inthis example is prepared by the method of Julia et al., cited above.

By following the procedure of this example and using the appropriatestarting material of formula IIa, together with the appropriate compoundof formula VI, other intermediates of formula VIIa are obtained.

EXAMPLE 9201-[2-(Dimethylamino)ethyl]-1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole[Ia, R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X = O and Y = CH₂ CH₂N(CH₃)₂ ]

A solution of1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-acetic acid ethylester (17.0 g), described in Example 916, in tetrahydrofuran (200 ml) isadded dropwise to a suspension of lithium aluminium hydride (5.0 g) intetrahydrofuran (150 ml). The mixture is heated at reflux for 2.5 hr.and then cooled and treated with a mixture of water-tetrahydrofuran (30ml- 150 ml). The mixture is filtered through celite and the filtrate isevaporated. The residue is purified by chromatography on silica gel.Elution with chloroform gives1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-ethanol.

A solution of the latter compound (6.5 g) in 75 ml of pyridine, cooledto 0° C, is treated with 10.0 g of p-toluenesulfonyl chloride. Theresulting solution is kept at 3° C overnight; thereafter, it is pouredinto ice water. The mixture is extracted with ether. The extract iswashed with water, dried and evaporated at low temperature to give thecorresponding tosylate. This material is dissolved in dimethylformamide(DMF, 80 ml) and dimethylamine (16 ml) is added. The mixture is heatedunder reflux for 1.5 hr. The DMF is evaporated and the residue isdissolved in chloroform. The chloroform solution is washed with waterand then evaporated to give the title compound, nmr (CDCl₃) δ 1.62, 2.15and 4.12, is obtained; the corresponding oxalic acid addition saltthereof having m.p. 139° -140° C., after crystallization fromisopropanol.

By following the same procedure but replacing dimethylamine with anequivalent amount of diethylamine,1-[2-(diethylaminoethyl]-1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole,nmr (CDCl₃) δ 1.63, 3.65 and 4.05, is obtained; the oxalic acid additionsalt thereof having m.p. 122° -124° C., after crystallization fromisopropanol.

By following the procedure of this example and using the appropriateester of formula VIIa (Z = COOR¹⁹ and Alk¹ --COOR¹⁹), together with theappropriate amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as definedin the first instance then other compounds of formula Ia are obtained.

EXAMPLE 9215-Ethyl-1-methyl-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydrothiopyrano[4,3-b]indole(Ia, R¹ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, R⁷ = C₂ H₅, X = S and Y = CH₂CH₂ N(CH₃)₂ ]

A mixture of sodium 2-[(1-ethyl-indol-2-yl)ethyl]thiosulfate (6 g),derived from 1-ethylindole-2-ethanol having nmr (CDCl₃) δ 1.26, 1.99,2.91, 3.86, 4.08, 6.27, 4-dimethylamino-2-butanone (3 g), toluene (10ml) and boron trifluoride etherate (10 ml) is heated at 80° for 4 hr.After cooling the reaction mixture is processed in the same manner asdescribed for the work-up of the N-formul derivative in Example 919 toafford the title compound, nmr (CDCl₃) δ 1.3 (t, J = 7, 3H), 1.7 (s,3H), 2.15 (s, 6H), 4.3 (q, J = 7, 2H).

EXAMPLE 922 (+)- or(-)-1-[2-(Dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole

Racemic1-[2-(Dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole,described in Example 915, is separated into its enatiomers by usingeither (+)- or (-)-mandelic acid. When the racemate is treated with(-)-mandelic acid a mixture of diastereomeric salts is obtained. Upontrituration of the mixture with water, the water-insoluble(-)-mandelate, [α]_(D) ²⁵ = 137° (MeOH), m.p. 110° - 113° C, separatesfrom the water-soluble (+)-mandelate, [α]_(D) ²⁵ = + 36.2° C (MeOH).Subsequent decomposition with dilute sodium hydroxide yields thecorresponding (+) or (-) free bases, i.e. the title compounds. The (+)base has [α]_(D) ²⁵ = + 43.1° (MeOH) and the (-) base has [α]_(D) ²⁵ = -44.5° (MeOH). Corresponding hydrochloric acid addition salts have m.p.224° -226° C, [α]_(D) ²⁵ = + 10.1° (MeOH) and m.p. 222° -224° C, [α]_(D)²⁵ = - 11.1° (MeOH), respectively.

We claim:
 1. A method of preventing and treating ulcers in warm bloodedanimals which comprises:administering to said mammal an effective doseof from about 0.1 to about 50 milligrams per kilogram of mammal weightper day of a compound selected from those of the formulae I and Ia##STR96## in which R¹ is lower alkyl or lower cycloalkyl; R², R³, R⁴ andR⁵ are the same or different selected from the group consisting ofhydrogen and lower alkyl; R⁶ is hydrogen, lower alkyl, hydroxy, loweralkoxy, lower alkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl,lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower)alkylradical of formula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selectedfrom the group consisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴R¹⁵, and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ areeither the same or different selected from the group consisting ofhydrogen and lower alkyl, or R⁸ is lower alkyl and R⁹ isp-chlorophenacyl, or R.sup. 8 and R⁹ together with the nitrogen atom towhich they are joined form a heterocyclic amine radical selected fromthe group consisting of 1-pyrrolidinyl, piperidino, morpholino, 1piperazinyl, 4-(lower alkyl)-1-piperazinyl and4-[hydroxy(lower)alkyl]-1-piperazinyl; X is oxy: and Y is lower alkyl,phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NR⁸R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ arehydrogen or lower alkyl and R⁸ and R⁹ are as defined herein; with theproviso that at least one of R⁷ and Y is --Alk--NR⁸ R⁹ and that in thecompounds of formula Ia, Y is --Alk NR⁸ R⁹ as defined herein; and thecorresponding acid addition salt with a pharmaceutically acceptableacid.
 2. The method of claim 1 in which the compound of formula I is1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,or a pharmaceutically acceptable acid addition salt thereof.
 3. Themethod of claim 1 in which the compound of formula I is1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,or a pharmaceutically acceptable acid addition salt thereof.
 4. Apharmaceutical composition, which comprises:a pharmaceuticallyacceptable carrier and from about 0.1 to about 50 milligrams of acompound selected from those of the formulae I and Ia ##STR97## in whichR¹ is lower alkyl or lower cycloalkyl; R², R³, R⁴ and R⁵ are the same ordifferent selected from the group consisting of hydrogen and loweralkyl; R⁶ is hydrogen, lower alkyl, hydroxy, lower alkoxy, loweralkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl, lower alkenyl,propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula--Alk--NR⁸ R⁹ wherein Alk is an alkylene selected from the groupconsisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ andR¹⁷ are hydrogen or lower alkyl, and R⁸ and R⁹ are either the same ordifferent selected from the group consisting of hydrogen and loweralkyl, or R⁸ is lower alkyl and R⁹ is p-chlorophenacyl, or R.sup. 8 andR⁹ together with the nitrogen atom to which they are joined form aheterocyclic amine radical selected from the group consisting of1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 4-(loweralkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl; X isoxy; and Y is lower alkyl, phenyl(lower)alkyl or an amino(lower)alkylradical of formula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selectedfrom the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹²R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ andR⁹ are as defined herein; with the proviso that at least one of R⁷ and Yis --Alk--NR⁸ R⁹ and that in the compounds of formula Ia, Y is --Alk NR⁸R⁹ as defined herein; and the corresponding acid addition salt with apharmaceutically acceptable acid.
 5. The composition of claim 4 in whichthe compound of formula I is1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,or the oxalic acid addition salt thereof.
 6. The composition of claim 4in which the compound of formula I is1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,or the hydrochloric acid addition salt thereof.
 7. The composition ofclaim 4 in which the compound of formula I is1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,or the hydrochloric acid addition salt thereof.
 8. The method of claim 1in which the compound of formula I is1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,or a pharmaceutically acceptable acid addition salt thereof.